JP7467332B2 - Fused Heterocyclic Derivatives as BCL-2 Inhibitors for the Treatment of Neoplastic Diseases - Google Patents
Fused Heterocyclic Derivatives as BCL-2 Inhibitors for the Treatment of Neoplastic Diseases Download PDFInfo
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- JP7467332B2 JP7467332B2 JP2020510610A JP2020510610A JP7467332B2 JP 7467332 B2 JP7467332 B2 JP 7467332B2 JP 2020510610 A JP2020510610 A JP 2020510610A JP 2020510610 A JP2020510610 A JP 2020510610A JP 7467332 B2 JP7467332 B2 JP 7467332B2
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- methyl
- tetrahydro
- piperazin
- pyrrolo
- pyrido
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Description
関連出願への相互参照
本出願は、2017年8月23日出願の米国特許仮出願第62/549,081号及び2018年1月9日出願の米国特許仮出願第62/615,007号の出願日の利益を主張する。上記の出願の各々の全体の内容は、参照により本明細書に組み込まれる。
CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of the filing dates of U.S. Provisional Application No. 62/549,081, filed August 23, 2017, and U.S. Provisional Application No. 62/615,007, filed January 9, 2018. The entire contents of each of the above applications are incorporated herein by reference.
アポトーシス、又はプログラム細胞死は、不必要な老齢の損傷細胞を除去するための主要な機序である、保存及び制御されたプロセスである。アポトーシスシグナル伝達をブロックする能力は、癌の主要な特徴であることから、腫瘍形成、腫瘍維持及び化学療法抵抗性にとって重要である[Hanahan, D. & Weinberg, R.A. The hallmarks of cancer. Cell、100巻、57~70頁(2000年)]。BCL-2ファミリーにおける死滅促進性(prodeath)タンパク質(例えば、BCL-2関連Xタンパク質(BAX)、BCL-2アンタゴニスト/キラー1(BAK)、BCL-2関連細胞死のアゴニスト(BAD)、BCL-2様11(BIM)、NOXA及びBCL-2結合成分3(PUMA))と、生存促進性(prosurvival)タンパク質(BCL-2、BCL-XL、BCL-2様2(BCL-W)、骨髄性細胞白血病配列1(MCL-1)及びBCL-2関連タンパク質A1(BFL-1))との間の動的結合相互作用が、プログラム細胞死へのコミットメントをコントロールする。これらの対抗する勢力間の均衡を変えることによって、癌細胞が正常なアポトーシスを弱め、生存優位性を獲得する1つの手段を得ている[Youle, R.J. & Strasser, A.、The BCL-2 protein family: opposing activities that mediate cell death. Nat. Rev. Mol. Cell Biol. 9巻、47~59頁(2008年)]。 Apoptosis, or programmed cell death, is a conserved and regulated process that is the primary mechanism for eliminating unwanted, old, damaged cells. The ability to block apoptotic signaling is a key hallmark of cancer and is therefore important for tumorigenesis, tumor maintenance, and chemotherapy resistance [Hanahan, D. & Weinberg, R.A. The hallmarks of cancer. Cell, 100, 57-70 (2000)]. Dynamic binding interactions between prodeath proteins in the BCL-2 family (e.g., BCL-2-associated X protein (BAX), BCL-2 antagonist/killer 1 (BAK), BCL-2-associated cell death agonist (BAD), BCL-2-like 11 (BIM), NOXA, and BCL-2-associated component 3 (PUMA)) and prosurvival proteins (BCL-2, BCL-XL, BCL-2-like 2 (BCL-W), myeloid cell leukemia sequence 1 (MCL-1), and BCL-2-associated protein A1 (BFL-1)) control the commitment to programmed cell death. By altering the balance between these opposing forces, cancer cells have one way of weakening normal apoptosis and gaining a survival advantage [Youle, R.J. & Strasser, A., The BCL-2 protein family: opposing activities that mediate cell death. Nat. Rev. Mol. Cell Biol. 9, 47-59 (2008)].
BCL-2は、最初に特定されたアポトーシス制御因子であり、もともとヒトB細胞リンパ腫中に存在するt(14;18)転座のブレークポイントからクローニングされた[Tsujimoto, Y.ら、Science、228巻、1440~1443頁(1985年); Cleary, M.L.ら、Cell、47巻、19~28頁(1986年); Boise, L.H.ら、Cell、74巻、597~608頁(1993年)]。このタンパク質は、複数のリンパ系悪性腫瘍の生存において主要な役割を有することが以前より示されている[Vaux, D.L.ら、pre-B cells.、Nature、335巻、440~442頁(1988年)]。Bcl-2タンパク質の過剰発現は、様々な癌及び免疫系の障害において、化学療法、臨床成果、疾患進行、全体的予後又はこれらの組合せに対する耐性に相関する。膀胱癌、脳癌、乳癌、骨髄癌、子宮頸癌、慢性リンパ球性白血病、結腸直腸癌、食道癌、肝細胞癌、リンパ芽球性白血病、濾胞性リンパ腫、T細胞又はB細胞起源のリンパ系悪性腫瘍、黒色腫、骨髄性白血病、骨髄腫、口腔癌、卵巣癌、非小細胞肺癌、前立腺癌、小細胞肺癌、脾臓癌などへのBcl-2タンパク質の関与は、WO 2005/049593として公開されたPCT/US2004/36770、及び、WO/2005/049594として公開されたPCT/US2004/37911に記載されている。免疫疾患及び自己免疫疾患におけるBcl-2タンパク質の関与は、Current Allergy and Asthma Reports、2003年、3巻、378~384頁; British Journal of Hematology、2000年、110巻(3号)、584~90頁; Blood、2000年、95巻(4号)、1283~92頁;及びNew England Journal of Medicine、2004年、351巻(14号)、1409~1418頁に記載されている。関節炎におけるBcl-2タンパク質の関与は、WO 2009/064938に開示されている。骨髄移植片拒絶におけるBcl-2タンパク質の関与は、US 2008-0182845A1に開示されている。すべては参照により本明細書に組み込まれる。 BCL-2 was the first identified regulator of apoptosis and was originally cloned from the breakpoint of the t(14;18) translocation present in human B cell lymphomas [Tsujimoto, Y. et al., Science, vol. 228, pp. 1440-1443 (1985); Cleary, M.L. et al., Cell, vol. 47, pp. 19-28 (1986); Boise, L.H. et al., Cell, vol. 74, pp. 597-608 (1993)]. This protein has previously been shown to play a key role in the survival of multiple lymphoid malignancies [Vaux, D.L. et al., pre-B cells., Nature, vol. 335, pp. 440-442 (1988)]. Overexpression of Bcl-2 protein correlates with resistance to chemotherapy, clinical outcome, disease progression, overall prognosis, or a combination of these in a variety of cancers and disorders of the immune system. The involvement of Bcl-2 protein in bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular carcinoma, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myeloid leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, pancreatic cancer, and the like, is described in PCT/US2004/36770, published as WO 2005/049593, and PCT/US2004/37911, published as WO/2005/049594. The involvement of Bcl-2 proteins in immune and autoimmune diseases has been described in Current Allergy and Asthma Reports, 2003, vol. 3, pp. 378-384; British Journal of Hematology, 2000, vol. 110(No. 3), pp. 584-90; Blood, 2000, vol. 95(No. 4), pp. 1283-92; and New England Journal of Medicine, 2004, vol. 351(No. 14), pp. 1409-1418. The involvement of Bcl-2 proteins in arthritis has been disclosed in WO 2009/064938. The involvement of Bcl-2 proteins in bone marrow graft rejection has been disclosed in US 2008-0182845A1, all of which are incorporated herein by reference.
最近10年間で、いくつかのBcl-2阻害剤、例えば、以下に示されているようなABT-737、ABT-263、及びABT-199などが特定され、癌治療のためのヒト臨床試験に入っている。 Over the last decade, several Bcl-2 inhibitors, such as ABT-737, ABT-263, and ABT-199 shown below, have been identified and are in human clinical trials for the treatment of cancer.
ABT-737は、核磁気共鳴(NMR)ベースのスクリーニング、並行合成及び構造ベースの断片ドラッグデザインにより発見された[Tillman Oltersdorfら、Nature、435巻、2005年、677頁]。ABT-737は、以前に報告された化合物よりも2~3桁強力な親和性を有する、抗アポトーシスタンパク質、Bcl-2、Bcl-XL及びBcl-wの小分子阻害剤である。機構研究は、ABT-737がアポトーシスプロセスを直接開始するのではなく、死亡シグナルの効果を向上し、化学療法薬及び放射線との相乗的細胞毒性を示すことを明らかにしている。ABT-737は、リンパ腫及び小細胞肺癌株からの細胞、並びに患者由来の初代細胞の単剤機序ベースの細胞死滅を示しており、動物モデルにおいてABT-737は、生存を改善し、確立した腫瘍の退縮を引き起こし、高いパーセンテージのマウスにおいて治癒をもたらしている。残念なことに、ABT-737は、経口的バイオアベイラビリティがなく、静脈内送達用のその製剤はその低い水性溶解性が妨げとなっている。 ABT-737 was discovered by nuclear magnetic resonance (NMR)-based screening, parallel synthesis and structure-based fragment drug design [Tillman Oltersdorf et al., Nature, Vol. 435, 2005, p. 677]. ABT-737 is a small molecule inhibitor of the anti-apoptotic proteins Bcl-2, Bcl-XL and Bcl-w with affinity 2-3 orders of magnitude stronger than previously reported compounds. Mechanistic studies reveal that ABT-737 does not directly initiate the apoptotic process, but rather enhances the efficacy of death signals and exhibits synergistic cytotoxicity with chemotherapeutic drugs and radiation. ABT-737 has demonstrated single-agent mechanism-based cell killing of cells from lymphoma and small cell lung cancer lines, as well as primary patient-derived cells, and in animal models ABT-737 has improved survival and caused regression of established tumors, resulting in cures in a high percentage of mice. Unfortunately, ABT-737 has no oral bioavailability, and its formulation for intravenous delivery is hindered by its poor aqueous solubility.
大規模なMedChemの取組み後、経口的バイオアベイラビリティがあるBcl-2阻害剤ABT-263(ナビトクラックス)が開発されている[Cheol-Min Parkら、J. Med. Chem.、2008年、51巻、6902~6915頁]。ABT-263は、Ki≦0.5nM、≦1nM及び≦1nMを有する、Bcl-xL、Bcl-2及びBcl-wの有力な阻害剤である。ABT-263は、SCLC H146細胞株に対して110nMのIC50を有する。H345異種移植片モデルにおいてABT-263が100mg/kg/日で投与された場合、TGI 80%であり、治療した腫瘍の20%が腫瘍容積の少なくとも50%の減少を示すという大幅な抗腫瘍効力が観察されている。ABT-263の経口投与は単独で、小細胞肺癌及び急性リンパ芽球性白血病の異種移植片モデルにおいて完全な腫瘍退縮を引き起こしている[Tse Cら、Cancer Res.、2008年、68巻(9号)、3421~3428頁]。しかし、臨床試験では、ABT-263(ナビトクラックス)によるBCL-XLの阻害は、循環している血小板の数の急速な、濃度依存性減少を誘発する。この機序ベースの血小板減少症は、患者における単剤ナビトクラックス治療の用量制限毒性であり、薬物濃度を非常に効果的な範囲へと推進させる能力を制限する。 After an extensive MedChem effort, an orally bioavailable Bcl-2 inhibitor ABT-263 (Navitoclax) has been developed [Cheol-Min Park et al., J. Med. Chem., 2008, 51, 6902-6915]. ABT-263 is a potent inhibitor of Bcl-xL, Bcl-2 and Bcl-w with Ki ≦0.5 nM, ≦1 nM and ≦1 nM. ABT-263 has an IC 50 of 110 nM against the SCLC H146 cell line. Substantial antitumor efficacy has been observed in the H345 xenograft model when ABT-263 is administered at 100 mg/kg/day, with a TGI of 80% and 20% of treated tumors showing at least a 50% reduction in tumor volume. Oral administration of ABT-263 alone has caused complete tumor regression in xenograft models of small cell lung cancer and acute lymphoblastic leukemia [Tse C et al., Cancer Res., 2008, 68(9):3421-3428]. However, in clinical trials, inhibition of BCL-XL with ABT-263 (navitoclax) induces a rapid, concentration-dependent decrease in the number of circulating platelets. This mechanism-based thrombocytopenia is the dose-limiting toxicity of single-agent navitoclax treatment in patients, restricting the ability to drive drug concentrations into a highly effective range.
よって、BCL-2選択的(BCL-XL温存)阻害剤であれば、リンパ系悪性腫瘍における効力を維持しながら、血小板減少症を実質的に減少させる結果となる。得られる治療濃度域の増加は、BCL-2依存性腫瘍型においてより大きなBCL-2抑制及び臨床効能をもたらすはずである。大規模なMedChemの取組み後、ABT-199(GDC-0199)の開発に成功した[Andrew J Souersら、Nature Medicine、19巻、22号、202頁、2013年]。ABT-199は、Ki<0.01nMを有し、Bcl-xL及びBcl-wとの対比で>4800倍の選択性があり、Mcl-1に対して活性のないBcl-2-選択的阻害剤である。ABT-199は、8nMのEC50で、RS4;11細胞を強力に阻害する。さらに、ABT-199は、シトクロムcの放出、カスパーゼ活性化、及びサブG0/G1 DNAの蓄積により、RS4;11細胞において急速なアポトーシスを誘発する。定量的免疫ブロットは、ABT-199に対する感受性が、NHL、DLBCL、MCL、AML及びALLの細胞株を含むBcl-2の発現と強く相関することを明らかにしている。ABT-199はまた、平均3.0nMのEC50で、CLLにおいてアポトーシスを誘発する。ABT-199の100mg/kgの単回用量は、RS4;11異種移植片において、95%の最大腫瘍成長阻害及び152%の腫瘍成長遅延を引き起こす。ABT-199はまた、単剤として又はベンダムスチン及び他の薬剤と併用して異種移植片成長(DoHH2、Granta-519)を阻害する。ヒト相I及びIIデータは、ABT-199が17p欠失を有するCLLに対して非常に効果的であることを示し、2016年FDAにより認可された。 Thus, a BCL-2 selective (BCL-XL sparing) inhibitor would result in a substantial reduction in thrombocytopenia while maintaining efficacy in lymphoid malignancies. The resulting increase in therapeutic window should lead to greater BCL-2 inhibition and clinical efficacy in BCL-2 dependent tumor types. After an extensive MedChem effort, ABT-199 (GDC-0199) was successfully developed [Andrew J Souers et al., Nature Medicine 19(22):202, 2013]. ABT-199 is a Bcl-2-selective inhibitor with a Ki<0.01 nM, >4800-fold selectivity over Bcl-xL and Bcl-w, and no activity against Mcl-1. ABT-199 potently inhibits RS4;11 cells with an EC50 of 8 nM. Furthermore, ABT-199 induces rapid apoptosis in RS4;11 cells by cytochrome c release, caspase activation, and accumulation of sub-G0/G1 DNA. Quantitative immunoblots reveal that sensitivity to ABT-199 strongly correlates with expression of Bcl-2, including NHL, DLBCL, MCL, AML, and ALL cell lines. ABT-199 also induces apoptosis in CLL with an average EC50 of 3.0 nM. A single dose of 100 mg/kg of ABT-199 causes 95% maximum tumor growth inhibition and 152% tumor growth delay in RS4;11 xenografts. ABT-199 also inhibits xenograft growth (DoHH2, Granta-519) as a single agent or in combination with bendamustine and other agents. Human phase I and II data showed that ABT-199 was highly effective against CLL with 17p deletion and it was approved by the FDA in 2016.
WO/2017/132474は新規クラスのBCL-2阻害剤を開示している。しかし、本技術分野においてより有力なBCL-2阻害剤の探索の継続に対して強い必要性が依然として存在する。 WO/2017/132474 discloses a novel class of BCL-2 inhibitors. However, there remains a strong need in the art for the continued search for more potent BCL-2 inhibitors.
第1の実施形態において、本発明は、式(A)の化合物若しくはそのN-酸化物、又は前記式(A)の化合物若しくはそのN-酸化物の薬学的に許容可能な塩、溶媒和物、多形、互変異性体、立体異性体、同位体形態、若しくはプロドラッグを提供し: In a first embodiment, the present invention provides a compound of formula (A) or an N-oxide thereof, or a pharma- ceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form, or prodrug of said compound of formula (A) or an N-oxide thereof:
Q1は、7員ヘテロシクロアルキル、7員ヘテロシクロアルケニル、又は7員ヘテロアリールであり、
Q2は、アリール又はヘテロアリールであり、
Q3は、シクロアルキル、シクロアルケニル、ヘテロシクロアルキル、ヘテロシクロアルケニル、アリール、又はヘテロアリールであり、
Q4は、
Q1 is a 7-membered heterocycloalkyl, a 7-membered heterocycloalkenyl, or a 7-membered heteroaryl;
Q2 is aryl or heteroaryl;
Q3 is cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl;
Q4 is,
R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、及びR12の各々は、独立に、H、D、アルキル、アルケニル、アルキニル、シクロアルキル、シクロアルケニル、ヘテロシクロアルキル、ヘテロシクロアルケニル、アリール、ヘテロアリール、ハロ、ニトロ、オキソ、シアノ、ORa、SRa、アルキル-Ra、NH(CH2)pRa、C(O)Ra、S(O)Ra、SO2Ra、C(O)ORa、OC(O)Ra、NRbRc、P(O)RbRc、アルキル-P(O)RbRc、C(O)N(Rb)Rc、N(Rb)C(O)Rc、-S(O)(=N(Rb))Rc、-N=S(O)RbRc、SO2N(Rb)Rc、又はN(Rb)SO2Rcであり、ここで前記シクロアルキル、シクロアルケニル、ヘテロシクロアルキル、ヘテロシクロアルケニル、アリール、ヘテロアリールは、場合により1つ以上のRdで置換されており、
Ra、Rb、Rc及びRdは、独立に、H、D、アルキル、アルケニル、アルキニル、ハロ、シアノ、アミン、ニトロ、ヒドロキシ、=O、C(O)NHOH、C(O)OH、C(O)NH2、アルコキシ、アルコキシアルキル、ハロアルキル、ヒドロキシアルキル、アミノアルキル、アルキルカルボニル、アルコキシカルボニル、アルキルカルボニルアミノ、アルキルアミノ、オキソ、ハロ-アルキルアミノ、シクロアルキル、シクロアルケニル、ヘテロシクロアルキル、ヘテロシクロアルケニル、アリール、又はヘテロアリールであり、ここで前記アルキル、シクロアルキル、シクロアルケニル、ヘテロシクロアルキル、ヘテロシクロアルケニル、アリール、ヘテロアリールは、場合により1つ以上のReで置換されており、
Reは、H、D、アルキル、アルケニル、アルキニル、ハロ、シアノ、アミン、ニトロ、ヒドロキシ、=O、C(O)NHOH、アルコキシ、アルコキシアルキル、ハロアルキル、ヒドロキシアルキル、アミノアルキル、アルキルカルボニル、アルコキシカルボニル、アルキルカルボニルアミノ、アルキルアミノ、オキソ、ハロ-アルキルアミノ、シクロアルキル、シクロアルケニル、ヘテロシクロアルキル、ヘテロシクロアルケニル、アリール、又はヘテロアリールであり、
Z1は、結合、(CH2)p、N(H)、O、S、C(O)、S(O2)、OC(O)、C(O)O、OSO2、S(O2)O、C(O)S、SC(O)、C(O)C(O)、C(O)N(H)、N(H)C(O)、S(O2)N(H)、N(H)S(O2)、OC(O)O、OC(O)S、OC(O)N(H)、N(H)C(O)O、N(H)C(O)S、N(H)C(O)N(H)、(CH2)pN(H)(CH2)q、(CH2)pN(H)C(O)(CH2)q、(CH2)pC(O)N(H)(CH2)q、OC(O)N(H)(CH2)p+1N(H)(CH2)q、二価アルケニル基、又は二価アルキニル基であり、
Lは、結合、アルキル、アルケニル、アルキニル、シクロアルキル、シクロアルケニル、ヘテロシクロアルキル、ヘテロシクロアルケニル、アリール、又はヘテロアリールであり、ここで前記アルキル、シクロアルキル、シクロアルケニル、ヘテロシクロアルキル、ヘテロシクロアルケニル、アリール、又はヘテロアリールは、場合により1つ以上のRdで置換されており、
Y、W、W1、及びW2の各々は、独立に、CH又はNであり、
W3はO又はN(Ra)であり、
VはN、C、又はCHであり、
R9基の2つは、それらが結合している原子と共に、場合によりシクロアルキル又はヘテロシクロアルキルを形成してもよく、ここでR9の前記シクロアルキル又はヘテロシクロアルキルは、場合により1つ以上のRdで置換されており、
R2基の2つは、それらが結合している原子と共に、場合によりシクロアルキル又はヘテロシクロアルキルを形成してもよく、ここでR2の前記シクロアルキル又はヘテロシクロアルキルは、場合により1つ以上のRdで置換されており、
R10基の2つは、それらが結合している原子と共に、場合によりシクロアルキル又はヘテロシクロアルキルを形成してもよく、ここでR10の前記シクロアルキル又はヘテロシクロアルキルは、場合により1つ以上のRdで置換されており、
R11及びR12基は、それらが結合している原子と共に、場合によりシクロアルキル又はヘテロシクロアルキルを形成してもよく、ここでR11又はR12の前記シクロアルキル又はヘテロシクロアルキルは、場合により1つ以上のRdで置換されており、
R10及びR2基は、それらが結合している原子と共に、場合によりシクロアルキル又はヘテロシクロアルキルを形成してもよく、ここでR10又はR2の前記シクロアルキル又はヘテロシクロアルキルは、場合により1つ以上のRdで置換されており、
R4及び-Z1-L-R6基は、それらが結合している原子と共に、場合によりシクロアルキル、シクロアルケニル、ヘテロシクロアルキル、ヘテロシクロアルケニル、アリール、又はヘテロアリールを形成してもよく、ここでR4の前記シクロアルキル、シクロアルケニル、ヘテロシクロアルキル、ヘテロシクロアルケニル、アリール、又はヘテロアリールは、場合により1つ以上のRdで置換されており、
Rb及びRc基は、それらが結合している原子と共に、場合によりシクロアルキル、又はヘテロシクロアルキルを形成してもよく、ここでRb及びRcの前記シクロアルキル又はヘテロシクロアルキルは、場合により1つ以上のReで置換されており、
Rd基の2つは、それらが結合している原子と共に、場合によりシクロアルキル、又はヘテロシクロアルキルを形成してもよく、ここでRdの前記シクロアルキル又はヘテロシクロアルキルは、場合により1つ以上のReで置換されており、
Re基の2つは、それらが結合している原子と共に、場合によりシクロアルキル又はヘテロシクロアルキルを形成してもよく、ここでReの前記シクロアルキル又はヘテロシクロアルキルは、場合によりH、D、アルキル、アルケニル、アルキニル、ハロ、シアノ、アミン、ニトロ、ヒドロキシ、C(O)NHOH、アルコキシ、アルコキシアルキル、ハロアルキル、ヒドロキシアルキル、アミノアルキル、アルキルカルボニル、アルコキシカルボニル、アルキルカルボニルアミノ、アルキルアミノ、オキソ、ハロ-アルキルアミノ、シクロアルキル、シクロアルケニル、ヘテロシクロアルキル、ヘテロシクロアルケニル、アリール、又はヘテロアリールから選択される1つ以上の基で置換されており、
j及びkの各々は、独立に、0、1、2、3、4、5、6、7、又は8であり、
m、n、p、q、及びrの各々は、独立に、0、1、2、3、又は4である。
R1 , R2 , R3 , R4 , R5 , R6 , R7 , R8, R9 , R10 , R11 , and R12 are each independently selected from H, D, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, halo, nitro, oxo, cyano, ORa , SRa , alkyl- Ra , NH ( CH2 ) pRa , C(O) Ra , S(O) Ra , SO2Ra , C(O) ORa , OC (O) Ra , NRbRc , P(O) RbRc , alkyl-P(O) RbRc , C(O)N ( Rb ) Rc , N( Rb )C( O ) Rc , -S(O)(=N( Rb ) )) Rc , -N=S(O )RbRc, SO2N(Rb)Rc, or N(Rb)SO2Rc , wherein said cycloalkyl , cycloalkenyl , heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl are optionally substituted with one or more Rd ;
R a , R b , R c and R d are independently H, D, alkyl, alkenyl, alkynyl, halo, cyano, amine, nitro, hydroxy, ═O, C(O)NHOH, C(O)OH, C(O)NH 2 , alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, halo-alkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl, wherein said alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl is optionally substituted with one or more Re ;
R e is H, D, alkyl, alkenyl, alkynyl, halo, cyano, amine, nitro, hydroxy, =O, C(O)NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, halo-alkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl;
Z1 is a bond, ( CH2 ) p , N(H), O, S, C(O), S( O2 ), OC(O), C(O)O, OSO2 , S( O2 )O, C(O)S, SC(O), C(O)C(O), C(O)N(H), N(H)C(O), S( O2 )N(H), N(H)S( O2 ), OC(O)O, OC(O)S, OC(O)N(H), N(H)C(O)O, N(H)C(O)S, N(H)C(O)N(H), ( CH2 ) pN (H)( CH2 ) q , ( CH2 ) pN (H)C(O)( CH2 ) q , ( CH2 ) pC (O)N(H)( CH2 ) q , OC(O)N(H)( CH2 ) p+1N (H)( CH2 ) q , a divalent alkenyl group, or a divalent alkynyl group;
L is a bond, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl, wherein said alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl is optionally substituted with one or more Rd ;
Each of Y, W, W1 , and W2 is independently CH or N;
W3 is O or N(R a );
V is N, C, or CH;
Two of the R 9 groups together with the atom to which they are attached may optionally form a cycloalkyl or heterocycloalkyl, where the cycloalkyl or heterocycloalkyl of R 9 is optionally substituted with one or more R d ;
Two of the R2 groups together with the atom to which they are attached may optionally form a cycloalkyl or heterocycloalkyl, where said cycloalkyl or heterocycloalkyl of R2 is optionally substituted with one or more Rd ;
Two of the R 10 groups together with the atom to which they are attached may optionally form a cycloalkyl or heterocycloalkyl, where the cycloalkyl or heterocycloalkyl of R 10 is optionally substituted with one or more R d ;
The R 11 and R 12 groups together with the atom to which they are attached may optionally form a cycloalkyl or heterocycloalkyl, wherein said cycloalkyl or heterocycloalkyl of R 11 or R 12 is optionally substituted with one or more R d ;
The R 10 and R 2 groups together with the atom to which they are attached may optionally form a cycloalkyl or heterocycloalkyl, wherein said cycloalkyl or heterocycloalkyl of R 10 or R 2 is optionally substituted with one or more R d ;
R4 and -Z1 - LR6 groups together with the atom to which they are attached may optionally form a cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl, wherein the cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl of R4 is optionally substituted with one or more Rd ;
The R b and R c groups together with the atom to which they are attached may optionally form a cycloalkyl, or heterocycloalkyl, where the cycloalkyl or heterocycloalkyl of R b and R c is optionally substituted with one or more Re ;
Two of the R d groups together with the atom to which they are attached may optionally form a cycloalkyl, or heterocycloalkyl, where the cycloalkyl or heterocycloalkyl of R d is optionally substituted with one or more Re ;
Two of the R e groups together with the atom to which they are attached may optionally form a cycloalkyl or heterocycloalkyl, where said cycloalkyl or heterocycloalkyl of R e is optionally substituted with one or more groups selected from H, D, alkyl, alkenyl, alkynyl, halo, cyano, amine, nitro, hydroxy, C(O)NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, halo-alkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl;
Each of j and k is independently 0, 1, 2, 3, 4, 5, 6, 7, or 8;
Each of m, n, p, q, and r is independently 0, 1, 2, 3, or 4.
第2の実施形態において、本発明は、式(B)により表される化合物若しくはそのN-酸化物、又は前記式(B)の化合物若しくはそのN-酸化物の薬学的に許容可能な塩、溶媒和物、多形、互変異性体、立体異性体、同位体形態、若しくはプロドラッグを提供し: In a second embodiment, the present invention provides a compound represented by formula (B) or an N-oxide thereof, or a pharma- ceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form, or prodrug of said compound of formula (B) or an N-oxide thereof:
Z2は、-O-、-CH2-、-C(O)-、-N(Ra)-、-S-、-S(O)-、-S(O2)-、-S(O)(=N(Ra))-、-P(O)(Ra)-であり、Z2のRaは、独立に、H、D、C1~C6アルキル、C2~C6アルケニル、C1~C6アルキルカルボニル、C1~C6アルコキシカルボニル、C3~C6シクロアルキル、5~8員単環式ヘテロシクロアルキル、C6~C14アリール、又は5~8員単環式ヘテロアリールであり、ここで前記C1~C6アルキル、C3~C6シクロアルキル、5~8員単環式ヘテロシクロアルキル、C6~C14アリール、5~8員単環式ヘテロアリールは、場合により1つ以上のReで置換されており、
Aは、-(CR2R2)r-又は-O-であり、rは、0、1、2、又は3であり、
各R2は、独立に、H、-(C1~C4)アルコキシ、場合により-(C1~C4)アルコキシで置換されている-(C1~C4)アルキルであるか、又は
R2基の2つは、それらが結合している同じ炭素原子と共に、-(C3~C6)シクロアルキル若しくは4~6員複素環式環を形成し、ここで-(C3~C6)シクロアルキル又は4~6員複素環式環は、場合により-(C1~C4)アルキル、-(C1~C4)ハロアルキル又はオキセタニルから選択される1つ以上の基で置換されており、残りの可変要素は第1の実施形態で定義されている通りである。
Z2 is -O-, -CH2- , -C(O)-, -N(R a )-, -S-, -S(O)-, -S( O2 )-, -S(O)(=N(R a ))-, -P(O)(R a )-, R a of Z2 is independently H, D, C1 - C6 alkyl, C2- C6 alkenyl, C1 - C6 alkylcarbonyl, C1 - C6 alkoxycarbonyl, C3 - C6 cycloalkyl, 5-8 membered monocyclic heterocycloalkyl, C6 - C14 aryl, or 5-8 membered monocyclic heteroaryl, wherein said C1 - C6 alkyl, C3 - C6 cycloalkyl, 5-8 membered monocyclic heterocycloalkyl, C6 - C14 aryl, 5-8 membered monocyclic heteroaryl are optionally substituted with one or more Re ;
A is -( CR2R2 ) r- or -O-, where r is 0, 1, 2 , or 3;
each R2 is independently H, -( C1 - C4 )alkoxy, -( C1 - C4 )alkyl optionally substituted with -( C1 - C4 )alkoxy;
Two of the R2 groups, together with the same carbon atom to which they are attached, form a -( C3 - C6 )cycloalkyl or a 4- to 6-membered heterocyclic ring, where the -( C3 - C6 )cycloalkyl or the 4- to 6-membered heterocyclic ring is optionally substituted with one or more groups selected from -( C1 - C4 )alkyl, -( C1 - C4 )haloalkyl or oxetanyl, and the remaining variables are as defined in the first embodiment.
第3の実施形態において、本発明は、式(C)により表される化合物若しくはそのN-酸化物、又は前記式(C)の化合物若しくはそのN-酸化物の薬学的に許容可能な塩、溶媒和物、多形、互変異性体、立体異性体、同位体形態、若しくはプロドラッグを提供し: In a third embodiment, the present invention provides a compound represented by formula (C) or an N-oxide thereof, or a pharma- ceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form, or prodrug of said compound of formula (C) or an N-oxide thereof:
第4の実施形態において、本発明は、式(D)により表される化合物若しくはそのN-酸化物、又は前記式(D)の化合物若しくはそのN-酸化物の薬学的に許容可能な塩、溶媒和物、多形、互変異性体、立体異性体、同位体形態、若しくはプロドラッグを提供し: In a fourth embodiment, the present invention provides a compound represented by formula (D) or an N-oxide thereof, or a pharma- ceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form, or prodrug of said compound of formula (D) or an N-oxide thereof:
R5は、独立に、ニトロ、ハロ、又は-SO2Raであり、R5のRaは、-(C1~C4)アルキル又は-(C1~C4)ハロアルキル(例えば、-CF3)であり、
Z1は、結合、NH、N(H)(CH2)q、O、S、又は-(C1~C4)アルキレンであり、qは、1、2、又は3であり、
Lは、非存在、又は場合により-(C3~C6)シクロアルキルで置換されている-(C1~C4)アルキレンであり、
R6は、H、D、-N(CH3)-(C1~C4)アルキレン-P(O)((C1~C4)アルコキシ)2、-P(O)(N(CH3)2)(OEt)、-P(O)(O-(C1~C4)アルキレン-O-CO-(C1~C4)アルキル)2、-(C3~C6)シクロアルキル、フェニル、5~7員ヘテロシクリル、8~10員二環式環であり、ここで-(C3~C6)シクロアルキル、フェニル、5~7員ヘテロシクリル、又は7~10員二環式環は、場合によりハロ、-OH、=O、-CN、-COOH、-NH2、-N(CH3)2、-NS(=O)(CH3)2、-SO2(C1~C4)アルキル、-(C1~C4)アルキル、-(C1~C4)アルコキシ、-(C1~C4)ハロアルコキシ、シクロプロピル、4~6員ヘテロシクリル、-CH2P(O)(OH)2、-CH2P(O)((C1~C4)アルコキシ)2、-P(O)((C1~C4)アルキル)2、又は-N=S(O)((C1~C4)アルキル)2から選択される1つ以上の基で置換されており、残りの可変要素は、第1、第2、及び/又は第3の実施形態で定義されている通りである。
R5 is independently nitro, halo, or -SO2R a , where R a of R5 is -( C1 - C4 )alkyl or -( C1 - C4 )haloalkyl (e.g., -CF3 );
Z 1 is a bond, NH, N(H)(CH 2 ) q , O, S, or -(C 1 -C 4 )alkylene, where q is 1, 2, or 3;
L is absent or -(C 1 -C 4 )alkylene optionally substituted with -(C 3 -C 6 )cycloalkyl;
R 6 is H, D, -N(CH 3 )-(C 1 -C 4 )alkylene-P(O)((C 1 -C 4 )alkoxy) 2 , -P(O)(N(CH 3 ) 2 )(OEt), -P(O)(O-(C 1 -C 4 )alkylene-O-CO-(C 1 -C 4 )alkyl) 2 , -(C 3 -C 6 )cycloalkyl, phenyl, 5- to 7-membered heterocyclyl, 8- to 10-membered bicyclic ring, where -(C 3 -C 6 )cycloalkyl, phenyl, 5- to 7-membered heterocyclyl, or 7- to 10-membered bicyclic ring is optionally selected from halo, -OH, ═O, -CN, -COOH, -NH 2 , -N(CH 3 ) 2 , -NS(═O)(CH 3 ) 2 , -SO 2 (C 1 - C4 )alkyl, -( C1 - C4 )alkyl, -( C1 - C4 )alkoxy, -( C1 - C4 )haloalkoxy, cyclopropyl, 4- to 6-membered heterocyclyl, -CH2P (O)(OH) 2 , -CH2P (O)(( C1 - C4 )alkoxy) 2 , -P(O)(( C1 - C4 )alkyl) 2 , or -N=S(O)(( C1 - C4 )alkyl) 2 , with the remaining variables being as defined in the first, second, and/or third embodiment.
第5の実施形態において、本発明は、構造式A、B、C、若しくはDによる化合物、若しくはそのN-酸化物、又は前記式の化合物若しくはそのN-酸化物の薬学的に許容可能な塩、溶媒和物、多形、互変異性体、立体異性体、同位体形態、若しくはプロドラッグを提供し、ここで、R9は、独立に、D、ハロ、-OH、CN、-NH2、=O、-(C1~C4)アルキル、-(C1~C4)アルコキシ、-(C1~C4)ハロアルキル、-(C1~C4)ヒドロキシアルキル、-(C3~C6)シクロアルキル、又は1,3-ジチオラニルであり、kは0、1、2、3、又は4であり、残りの可変要素は、第1、第2、第3、及び/又は第4の実施形態で定義されている通りである。 In a fifth embodiment, the present invention provides a compound according to structural formula A, B, C, or D, or an N-oxide thereof, or a pharma- ceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form, or prodrug of the compound of said formula or N-oxide thereof, wherein R9 is independently D, halo, -OH, CN, -NH2 , =O, -( C1 - C4 )alkyl, -( C1 - C4 )alkoxy, -( C1 - C4 )haloalkyl, -( C1 - C4 )hydroxyalkyl, -( C3 - C6 )cycloalkyl, or 1,3-dithiolanyl, k is 0, 1, 2, 3, or 4, and the remaining variables are as defined in the first, second, third, and/or fourth embodiment.
第6の実施形態において、本発明は、構造式A、B、C、若しくはDによる化合物、若しくはそのN-酸化物、又は前記式A、B、C、若しくはDの化合物若しくはそのN-酸化物の薬学的に許容可能な塩、溶媒和物、多形、互変異性体、立体異性体、同位体形態、若しくはプロドラッグを提供し、ここで、Aは-CH2-又は-O-であり、残りの可変要素は、第1、第2、第3、第4、及び/又は第5の実施形態で定義されている通りである。 In a sixth embodiment, the present invention provides a compound according to structural formula A, B, C, or D, or an N-oxide thereof, or a pharma- ceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form, or prodrug of the compound of formula A, B, C, or D, or an N-oxide thereof, wherein A is -CH2- or -O-, and the remaining variables are as defined in the first, second, third, fourth, and/or fifth embodiment.
第7の実施形態において、本発明は、構造式A、B、C、若しくはDによる化合物、若しくはそのN-酸化物、又は前記式A、B、C、若しくはDの化合物若しくはそのN-酸化物の薬学的に許容可能な塩、溶媒和物、多形、互変異性体、立体異性体、同位体形態、若しくはプロドラッグを提供し、ここで、各R2は、独立に、-CH3であり、nは0又は2であり、残りの可変要素は、第1、第2、第3、第4、第5及び/又は第6の実施形態で定義されている通りである。 In a seventh embodiment, the present invention provides a compound according to structural formula A, B, C, or D, or an N-oxide thereof, or a pharma- ceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form, or prodrug of said compound of formula A, B, C, or D, or an N-oxide thereof, wherein each R2 is independently -CH3 , n is 0 or 2, and the remaining variables are as defined in the first, second, third, fourth, fifth, and/or sixth embodiments.
第8の実施形態において、本発明は、構造式A、B、C、若しくはDによる化合物、若しくはそのN-酸化物、又は前記式A、B、C、若しくはDの化合物若しくはそのN-酸化物の薬学的に許容可能な塩、溶媒和物、多形、互変異性体、立体異性体、同位体形態、若しくはプロドラッグを提供し、ここで、Z2は-O-であり、残りの可変要素は、第1、第2、第3、第4、第5、第6及び/又は第7の実施形態で定義されている通りである。 In an eighth embodiment, the present invention provides a compound according to structural formula A, B, C, or D, or an N-oxide thereof, or a pharma- ceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form, or prodrug of said compound of formula A, B, C, or D, or an N-oxide thereof, wherein Z2 is -O-, and the remaining variables are as defined in the first, second, third, fourth, fifth, sixth, and/or seventh embodiment.
第9の実施形態において、本発明は、構造式A、B、C、若しくはDによる化合物、若しくはそのN-酸化物、又は前記式A、B、C、若しくはDの化合物若しくはそのN-酸化物の薬学的に許容可能な塩、溶媒和物、多形、互変異性体、立体異性体、同位体形態、若しくはプロドラッグを提供し、ここで、R1は、ハロ、例えば、Clであり、残りの可変要素は、第1、第2、第3、第4、第5、第6、第7及び/又は第8の実施形態で定義されている通りである。 In a ninth embodiment, the invention provides a compound according to structural formula A, B, C, or D, or an N-oxide thereof, or a pharma- ceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form, or prodrug of said compound of formula A, B, C, or D, or an N-oxide thereof, wherein R1 is halo, e.g., Cl, and the remaining variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, and/or eighth embodiment.
第10の実施形態において、本発明は、構造式A、B、C、若しくはDによる化合物、若しくはそのN-酸化物、又は前記式A、B、C、若しくはDの化合物若しくはそのN-酸化物の薬学的に許容可能な塩、溶媒和物、多形、互変異性体、立体異性体、同位体形態、若しくはプロドラッグを提供し、ここで、R5はニトロであり、残りの可変要素は、第1、第2、第3、第4、第5、第6、第7、第8及び/又は第9の実施形態で定義されている通りである。 In a tenth embodiment, the present invention provides a compound according to structural formula A, B, C, or D, or an N-oxide thereof, or a pharma- ceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form, or prodrug of said compound of formula A, B, C, or D, or an N-oxide thereof, wherein R5 is nitro, and the remaining variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, and/or ninth embodiment.
第11の実施形態において、本発明は、構造式A、B、C、若しくはDによる化合物、若しくはそのN-酸化物、又は前記式A、B、C、若しくはDの化合物若しくはそのN-酸化物の薬学的に許容可能な塩、溶媒和物、多形、互変異性体、立体異性体、同位体形態、若しくはプロドラッグを提供し、ここで、Z1は、非存在、NH又はOであり、残りの可変要素は、第1、第2、第3、第4、第5、第6、第7、第8、第9及び/又は第10の実施形態で定義されている通りである。 In an eleventh embodiment, the present invention provides a compound according to structural formula A, B, C, or D, or an N-oxide thereof, or a pharma- ceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form, or prodrug of said compound of formula A, B, C, or D, or an N-oxide thereof, wherein Z1 is absent, NH, or O, and the remaining variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, and/or tenth embodiment.
第12の実施形態において、本発明は、構造式A、B、C、若しくはDによる化合物、若しくはそのN-酸化物、又は前記式A、B、C、若しくはDの化合物若しくはそのN-酸化物の薬学的に許容可能な塩、溶媒和物、多形、互変異性体、立体異性体、同位体形態、若しくはプロドラッグを提供し、ここで、Z2は、-O-、-CH2-、-C(O)-、-NH-、-N-(オキセタニル)-、-S-、-S(O)-、-S(O2)-、-S(O)(=NH)-、-S(O)(=NCH3)-、又は-P(O)(CH3)-であり、残りの可変要素は、第1、第2、第3、第4、第5、第6、第7、第8、第9、第10及び/又は第11の実施形態で定義されている通りである。 In a twelfth embodiment, the present invention provides a compound according to structural formula A, B, C, or D, or an N-oxide thereof, or a pharma- ceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form, or prodrug of the compound of formula A, B, C, or D, or an N-oxide thereof, wherein Z2 is -O-, -CH2- , -C(O)-, -NH-, -N-(oxetanyl)-, -S-, -S(O)-, -S( O2 )-, -S(O)(=NH)-, -S(O)(= NCH3 )-, or -P(O)( CH3 )-, and the remaining variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth and/or eleventh embodiments.
第13の実施形態において、本発明は、構造式A、B、C、若しくはDによる化合物、若しくはそのN-酸化物、又は前記式A、B、C、若しくはDの化合物若しくはそのN-酸化物の薬学的に許容可能な塩、溶媒和物、多形、互変異性体、立体異性体、同位体形態、若しくはプロドラッグを提供し、ここで、R6は、H、D、-(C3~C6)シクロアルキル、フェニル、テトラヒドロ-2H-ピラニル、又は1,4-ジオキサニルであり、-(C3~C6)シクロアルキル、フェニル、テトラヒドロ-2H-ピラニル又は1,4-ジオキサニルは、場合によりハロゲン、-OH、=O、-(C1~C4)アルキル、又は-(C1~C4)アルコキシから選択される1又は2つの基で置換されており、残りの可変要素は、第1、第2、第3、第4、第5、第6、第7、第8、第9、第10、第11及び/又は第12の実施形態で定義されている通りである。 In a thirteenth embodiment, the present invention provides a compound according to structural formula A, B, C, or D, or an N-oxide thereof, or a pharma- ceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form, or prodrug of said compound of formula A, B, C, or D, or an N-oxide thereof, wherein R6 is H, D, -( C3 - C6 )cycloalkyl, phenyl, tetrahydro-2H-pyranyl, or 1,4-dioxanyl, and -( C3 - C6 )cycloalkyl, phenyl, tetrahydro-2H-pyranyl, or 1,4-dioxanyl is optionally halogen, -OH, =O, -( C1 - C4 )alkyl, or -( C1 - C4) alkyl. ) alkoxy, and the remaining variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh and/or twelfth embodiment.
第14の実施形態において、本発明は、構造式A、B、C、若しくはDによる化合物、若しくはそのN-酸化物、又は前記式A、B、C、若しくはDの化合物若しくはそのN-酸化物の薬学的に許容可能な塩、溶媒和物、多形、互変異性体、立体異性体、同位体形態、若しくはプロドラッグを提供し、ここで、R6は、テトラヒドロ-2H-ピラニル又は1,4-ジオキサニルであり、テトラヒドロ-2H-ピラニル又は1,4-ジオキサニルは、場合により1又は2つのハロゲンで置換されており、残りの可変要素は、第1、第2、第3、第4、第5、第6、第7、第8、第9、第10、第11、第12及び/又は第13の実施形態で定義されている通りである。 In a fourteenth embodiment, the present invention provides a compound according to structural formula A, B, C, or D, or an N-oxide thereof, or a pharma- ceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form, or prodrug of said compound of formula A, B, C, or D, or an N-oxide thereof, wherein R6 is tetrahydro-2H-pyranyl or 1,4-dioxanyl, which is optionally substituted with one or two halogens, and the remaining variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, and/or thirteenth embodiments.
例えば、構造式A、B、C、若しくはDによる化合物、若しくはそのN-酸化物、又は前記式A、B、C、若しくはDの化合物若しくはそのN-酸化物の薬学的に許容可能な塩、溶媒和物、多形、互変異性体、立体異性体、同位体形態、若しくはプロドラッグにおいて、Z1は-NH-であり、Lは-CH2-であり、R6は、場合により1又は2つのハロゲン基で置換されているテトラヒドロ-2H-ピラニル又は1,4-ジオキサニルであり、好ましくは、Aは-CH2-又は-O-であり、R1はClであり、R5はニトロであり、Z2は-O-であり、各R2は独立に-CH3であり、nは0又は2であり、R9はメチル(kは1である)又はハロ(kは2、例えば、ジフルオロである)である。 For example, in a compound according to structural formula A, B, C, or D, or an N-oxide thereof, or a pharma- ceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form, or prodrug of said compound of formula A, B, C, or D, or an N-oxide thereof, Z1 is -NH-, L is -CH2- , R6 is tetrahydro-2H-pyranyl or 1,4-dioxanyl, optionally substituted with one or two halogen groups, preferably, A is -CH2- or -O-, R1 is Cl, R5 is nitro, Z2 is -O-, each R2 is independently -CH3 , n is 0 or 2, and R9 is methyl (k is 1) or halo (k is 2, e.g., difluoro).
非修飾化合物と比較して改善された(例えば、向上した、より高い)医薬溶解性、安定性、バイオアベイラビリティ、及び/又は治療指数を有する修飾を含む、そのような化合物のいずれか1つの修飾化合物も考えられる。例示的な修飾物の例としては、(限定はされないが)適用可能なプロドラッグ誘導体、及び重水素富化化合物が挙げられる。 Modified compounds of any one of such compounds are also contemplated, including modifications that have improved (e.g., enhanced, higher) pharmaceutical solubility, stability, bioavailability, and/or therapeutic index compared to the unmodified compound. Exemplary modifications include (but are not limited to) applicable prodrug derivatives, and deuterium-enriched compounds.
新生物疾患の治療における使用、それらの治療上の使用、及び疾患/病気を治療するための薬剤の製造における化合物の使用のための本明細書に記載の化合物の1つ以上(例えば、式(A)~(D)のいずれか1つ、又はその薬学的に許容可能な塩、溶媒和物、多形、互変異性体、立体異性体、同位体形態、若しくはプロドラッグ又はそのN-酸化物)、その修飾物、及び/又は塩、並びに薬学的に許容可能な希釈剤又は担体を含有する医薬組成物も、本発明の範囲内である。 Also within the scope of the invention are pharmaceutical compositions containing one or more of the compounds described herein (e.g., any one of formulas (A)-(D), or a pharma- ceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form, or prodrug or N-oxide thereof), modifications, and/or salts thereof, and a pharma- ceutically acceptable diluent or carrier for use in the treatment of neoplastic diseases, their therapeutic uses, and use of the compounds in the manufacture of a medicament for treating a disease/condition.
本発明は、有効量の本明細書に記載の本発明の1つ以上の化合物(例えば、式(A)~(D)のいずれか1つ、又はその薬学的に許容可能な塩、溶媒和物、多形、互変異性体、立体異性体、同位体形態、若しくはプロドラッグ又はそのN-酸化物)、その修飾物、及び/又は塩、或いは本発明の化合物(複数可)を含む医薬組成物を、それを必要とする対象に投与するステップを含む、新生物疾患、自己免疫疾患、又は神経変性疾患を治療する方法にも関する。 The present invention also relates to a method of treating a neoplastic disease, an autoimmune disease, or a neurodegenerative disease, comprising administering to a subject in need thereof an effective amount of one or more compounds of the present invention (e.g., any one of Formulas (A)-(D), or a pharma- ceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form, or prodrug thereof, or N-oxide thereof), modifications, and/or salts thereof, or a pharmaceutical composition comprising a compound(s) of the present invention.
特定の実施形態において、新生物疾患、自己免疫疾患、又は神経変性疾患は、異常な(例えば、向上した、又は増加した)Bcl-2活性によって特徴づけられる。例えば、新生物疾患は血液悪性腫瘍又は固形腫瘍を含む癌であってよく、自己免疫疾患はI型糖尿病であってよく、神経変性疾患は統合失調症であってよい。 In certain embodiments, the neoplastic disease, autoimmune disease, or neurodegenerative disease is characterized by aberrant (e.g., improved or increased) Bcl-2 activity. For example, the neoplastic disease can be cancer, including hematological malignancies or solid tumors, the autoimmune disease can be type I diabetes, and the neurodegenerative disease can be schizophrenia.
特定の実施形態において、新生物疾患は、骨髄腫、多発性骨髄腫、リンパ腫、濾胞性リンパ腫(FL)、非ホジキンリンパ腫、白血病、急性白血病、急性リンパ芽球性白血病(ALL)(例えば、BCL-2依存性ALL及び小児ALL)、慢性リンパ芽球性白血病(CLL)(例えば、再発性/不応性CLL、del(17p)CLL)、慢性骨髄性白血病(CML)(例えば、急性転化CML)、マントル細胞リンパ腫(MCL)、びまん性大細胞型B細胞リンパ腫、肺癌、例えば、小細胞肺癌(SCLC)、黒色腫、乳癌、又は前立腺癌(それらの薬物耐性癌を含む)である。 In certain embodiments, the neoplastic disease is myeloma, multiple myeloma, lymphoma, follicular lymphoma (FL), non-Hodgkin's lymphoma, leukemia, acute leukemia, acute lymphoblastic leukemia (ALL) (e.g., BCL-2-dependent ALL and childhood ALL), chronic lymphoblastic leukemia (CLL) (e.g., relapsed/refractory CLL, del(17p)CLL), chronic myeloid leukemia (CML) (e.g., blast crisis CML), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma, lung cancer, e.g., small cell lung cancer (SCLC), melanoma, breast cancer, or prostate cancer (including drug-resistant cancers thereof).
特定の実施形態において、方法は、新生物疾患を治療するのに有効な1つ以上のさらなる治療(複数可)、例えば、手術、放射線療法、化学療法剤(例えば、ベンダムスチン、NL-101(7-(5-(ビス(2-クロロエチル)アミノ)-1-メチル-1H-ベンゾ[d]イミダゾール-2-イル)-N-ヒドロキシヘプタンアミド)、シスプラチン、カルボプラチン、エトポシド、トポテカン)、標的療法(例えば、抗CD20抗体、例えば、リツキシマブ、ブルトンチロシンキナーゼ阻害剤、例えば、イブルチニブ及びアカラブルチニブ(ACP-196)、PI3Kδ阻害剤、例えば、イデラリシブ);抗体薬物コンジュゲート又はADC(例えば、抗CD30 ADCブレンツキシマブベドチン)、免疫療法(例えば、ペムブロリズマブ及びニボルマブを含む抗PD-1抗体、又はアテゾリズマブ、デュルバルマブ、及びアベルマブを含む抗PD-L1抗体)、又はCAR-T療法(例えば、チサゲンレクルユーセル、アキシカブタゲンシロロイセル)を投与することをさらに含む。 In certain embodiments, the method further comprises administering to the patient one or more additional treatment(s) effective to treat the neoplastic disease, such as surgery, radiation therapy, chemotherapeutic agents (e.g., bendamustine, NL-101 (7-(5-(bis(2-chloroethyl)amino)-1-methyl-1H-benzo[d]imidazol-2-yl)-N-hydroxyheptanamide), cisplatin, carboplatin, etoposide, topotecan), targeted therapy (e.g., anti-CD20 antibodies, e.g., rituximab, Bruton's tyrosine kinase inhibitors, e.g., ibrutinib and acalabrutinib (ACP-196), PI3Kδ inhibitors, e.g., idelalisib); antibody drug conjugates or ADCs (e.g., anti-CD30 ADC brentuximab vedotin), immunotherapy (e.g., anti-PD-1 antibodies, including pembrolizumab and nivolumab, or anti-PD-L1 antibodies, including atezolizumab, durvalumab, and avelumab), or CAR-T therapy (e.g., tisagenlecleucel, axicabtagene ciloleucel).
上記参照された疾患又は状態の治療のための薬剤の調製のための、1つ以上の本発明の化合物、若しくはその薬学的に許容可能な塩、又は1つ以上の本発明の化合物を含む医薬組成物の使用も本明細書に提供されている。 Also provided herein is the use of one or more compounds of the invention, or pharma- ceutically acceptable salts thereof, or a pharmaceutical composition comprising one or more compounds of the invention, for the preparation of a medicament for the treatment of the above-referenced diseases or conditions.
別の実施形態において、上記参照された疾患又は状態の治療における使用のための、本発明の化合物、若しくはその薬学的に許容可能な塩、又は開示化合物の1つ以上を含む医薬組成物が本明細書に提供されている。 In another embodiment, provided herein is a compound of the present invention, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising one or more of the disclosed compounds, for use in the treatment of the above-referenced diseases or conditions.
本発明の1つ以上の実施形態の詳細を以下の説明に示す。本発明の他の特徴、目的、及び利点は、説明から及び特許請求の範囲から明らかとなる。実施例及び当初の特許請求の範囲に記載される任意の具体的な特徴を含めた、本明細書に記載の本発明のあらゆる実施形態/特徴(化合物、医薬組成物、作製/使用の方法など)は、適用不可能でない限り又は明確に否定されない限り、互いに組み合わせることができることを理解するべきである。 The details of one or more embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and from the claims. It should be understood that all embodiments/features of the invention described herein (compounds, pharmaceutical compositions, methods of making/using, etc.), including any specific features described in the examples and initial claims, can be combined with each other unless inapplicable or expressly denied.
本明細書に記載の例示的な化合物としては、限定はされないが、以下が挙げられる:
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
(R)-N-((4-(((1,4-ジオキサン-2-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
(S)-N-((4-(((1,4-ジオキサン-2-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
(S)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(4-メチル-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
N-((4-((((S)-1,4-ジオキサン-2-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-((S)-4-メチル-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
N-((4-((((R)-1,4-ジオキサン-2-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-((S)-4-メチル-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
(R)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(4-メチル-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
N-((4-((((S)-1,4-ジオキサン-2-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-((R)-4-メチル-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
N-((4-((((R)-1,4-ジオキサン-2-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-((R)-4-メチル-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
(S)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(4,4-ジフルオロ-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-(((2-フルオロ-1,4-ジオキサン-2-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミド、
(R)-N-((4-(((1,4-ジオキサン-2-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(4,4-ジフルオロ-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(4,4-ジフルオロ-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,3-ジメチル-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)-2-(4-(トリフルオロメチル)-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
(S)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)-2-(4-(トリフルオロメチル)-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
(R)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)-2-(3-(トリフルオロメチル)-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
(S)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3-シアノ-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
(R)-2-(3-アミノ-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
(R)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3-メトキシ-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
(R)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3-メチル-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
(S)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3-ヒドロキシ-3-メチル-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
(S)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3-メチル-3-(トリフルオロメチル)-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
(R)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3-シアノ-3-メチル-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
(R)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(2-メチル-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
Exemplary compounds described herein include, but are not limited to, the following:
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
(R)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
(S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
(S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
N-((4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-((S)-4-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
N-((4-((((R)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-((S)-4-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
(R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
N-((4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-((R)-4-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
N-((4-((((R)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-((R)-4-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
(S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4,4-difluoro-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((2-fluoro-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,
(R)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4,4-difluoro-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4,4-difluoro-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,3-dimethyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2-(4-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
(S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2-(4-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
(R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2-(3-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
(S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-cyano-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
(R)-2-(3-amino-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
(R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methoxy-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
(R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
(S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-hydroxy-3-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
(S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methyl-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
(R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-cyano-3-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
(R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
(S)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)-2-(2-(トリフルオロメチル)-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]チアゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,3-ジフルオロ-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]チアゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3-ヒドロキシ-3-メチル-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]チアゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3-シアノ-3-メチル-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]チアゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,3-ジフルオロ-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
(S)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3-シアノ-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-(((4-フルオロテトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミド、
(R)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-N-((4-(((4-フルオロテトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-2-(3-ヒドロキシ-3-メチル-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル-3,3-d2)-N-((4-(((4-フルオロテトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミド、
(R)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-N-((4-(((4-フルオロテトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-2-(3-メチル-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(4,4-ジメチル-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-(((4-フルオロテトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミド、
(R)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-N-((4-(((4-フルオロテトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-2-(2-メチル-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)-2-(2H,4H-スピロ[ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-3,2'-[1,3]ジチオラン]-1(7H)-イル)ベンズアミド、
(R)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,3-ジフルオロ-4-メチル-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)-2-(6,7,8,9-テトラヒドロピロロ[3',2':5,6]ピリド[3,2-b]アゼピン-5(1H)-イル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル-3,3,4,4-d4)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)-2-(3,4,5,7-テトラヒドロピロロ[3',2':5,6]ピリド[2,3-b][1,4]ジアゼピン-1(2H)-イル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)-2-(4-オキソ-3,4,5,7-テトラヒドロピロロ[3',2':5,6]ピリド[2,3-b][1,4]ジアゼピン-1(2H)-イル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(5-(メチルイミノ)-5-オキシド-3,4,5,7-テトラヒドロ-5l4-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]チアゼピン-1(2H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(2',3'-ジヒドロスピロ[シクロプロパン-1,4'-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン]-1'(7'H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-3-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-((2-モルホリノエチル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミド
(R)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-(((4-メチルモルホリン-2-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミド、
(R)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((4-(オキセタン-3-イル)モルホリン-2-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-(((4-ヒドロキシシクロヘキシル)メチル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-((((1r,4r)-4-メトキシシクロヘキシル)メチル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミド、
(S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2-(2-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]thiazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,3-difluoro-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]thiazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-hydroxy-3-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]thiazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-cyano-3-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]thiazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,3-difluoro-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
(S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-cyano-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,
(R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(3-hydroxy-3-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl-3,3-d2)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,
(R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(3-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4,4-dimethyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,
(R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(2-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2-(2H,4H-spiro[pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine-3,2'-[1,3]dithiolane]-1(7H)-yl)benzamide,
(R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,3-difluoro-4-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2-(6,7,8,9-tetrahydropyrrolo[3',2':5,6]pyrido[3,2-b]azepin-5(1H)-yl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl-3,3,4,4-d4)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2-(3,4,5,7-tetrahydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]diazepin-1(2H)-yl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2-(4-oxo-3,4,5,7-tetrahydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]diazepin-1(2H)-yl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(5-(methylimino)-5-oxido-3,4,5,7-tetrahydro-514-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]thiazepin-1(2H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2',3'-dihydrospiro[cyclopropane-1,4'-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine]-1'(7'H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-3-yl)methyl)amino)phenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-((2-morpholinoethyl)amino)-3-nitrophenyl)sulfonyl)benzamide
(R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((4-methylmorpholin-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,
(R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((4-(oxetan-3-yl)morpholin-2-yl)methyl)amino)phenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((4-hydroxycyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((1r,4r)-4-methoxycyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-((((1s,4s)-4-ヒドロキシ-4-メチルシクロヘキシル)メチル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-((((1s,4s)-4-エチル-4-ヒドロキシシクロヘキシル)メチル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-((1-(テトラヒドロ-2H-ピラン-4-イル)ピペリジン-4-イル)アミノ)フェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-(((1s,4s)-4-モルホリノシクロヘキシル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-N-((4-((4-(シクロプロピルアミノ)シクロヘキシル)アミノ)-3-ニトロフェニル)スルホニル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-N-((4-(((4,4-ジフルオロシクロヘキシル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-((テトラヒドロ-2H-ピラン-4-イル)メトキシ)フェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-((テトラヒドロ-2H-ピラン-3-イル)メトキシ)フェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-(2-モルホリノエトキシ)-3-ニトロフェニル)スルホニル)ベンズアミド、
(S)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-((4-メチルモルホリン-2-イル)メトキシ)-3-ニトロフェニル)スルホニル)ベンズアミド、
(S)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-((4-(オキセタン-3-イル)モルホリン-2-イル)メトキシ)フェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-((4-ヒドロキシシクロヘキシル)メトキシ)-3-ニトロフェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-(((1r,4r)-4-メトキシシクロヘキシル)メトキシ)-3-ニトロフェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-(((1s,4s)-4-ヒドロキシ-4-メチルシクロヘキシル)メトキシ)-3-ニトロフェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-(((1s,4s)-4-エチル-4-ヒドロキシシクロヘキシル)メトキシ)-3-ニトロフェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-((1-(テトラヒドロ-2H-ピラン-4-イル)ピペリジン-4-イル)オキシ)フェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-(((1s,4s)-4-モルホリノシクロヘキシル)オキシ)-3-ニトロフェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-N-((4-((4-(シクロプロピルアミノ)シクロヘキシル)オキシ)-3-ニトロフェニル)スルホニル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-N-((4-((4,4-ジフルオロシクロヘキシル)メトキシ)-3-ニトロフェニル)スルホニル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
4-(4-((2-(4-クロロフェニル)シクロペンタ-1-エン-1-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
4-(4-((2-(4-クロロフェニル)シクロヘプタ-1-エン-1-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
4-(4-((4-(4-クロロフェニル)-6,6-ジメチル-5,6-ジヒドロ-2H-ピラン-3-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-4-(メトキシメチル)-4-メチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-5-フルオロ-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((5-ニトロ-6-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)ピリジン-3-イル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)-3-((トリフルオロメチル)スルホニル)フェニル)スルホニル)ベンズアミド、
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((1s,4s)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((1s,4s)-4-ethyl-4-hydroxycyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-((1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)amino)phenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((1s,4s)-4-morpholinocyclohexyl)amino)-3-nitrophenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((4-(cyclopropylamino)cyclohexyl)amino)-3-nitrophenyl)sulfonyl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4,4-difluorocyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-3-yl)methoxy)phenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(2-morpholinoethoxy)-3-nitrophenyl)sulfonyl)benzamide,
(S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-((4-methylmorpholin-2-yl)methoxy)-3-nitrophenyl)sulfonyl)benzamide,
(S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-((4-(oxetan-3-yl)morpholin-2-yl)methoxy)phenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-((4-hydroxycyclohexyl)methoxy)-3-nitrophenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((1r,4r)-4-methoxycyclohexyl)methoxy)-3-nitrophenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((1s,4s)-4-hydroxy-4-methylcyclohexyl)methoxy)-3-nitrophenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((1s,4s)-4-ethyl-4-hydroxycyclohexyl)methoxy)-3-nitrophenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-((1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)oxy)phenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((1s,4s)-4-morpholinocyclohexyl)oxy)-3-nitrophenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((4-(cyclopropylamino)cyclohexyl)oxy)-3-nitrophenyl)sulfonyl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((4,4-difluorocyclohexyl)methoxy)-3-nitrophenyl)sulfonyl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
4-(4-((2-(4-chlorophenyl)cyclopent-1-en-1-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
4-(4-((2-(4-chlorophenyl)cyclohept-1-en-1-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-4-(methoxymethyl)-4-methyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-5-fluoro-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((5-nitro-6-(((tetrahydro-2H-pyran-4-yl)methyl)amino)pyridin-3-yl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide,
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(7,8-ジヒドロ-3H-イミダゾ[4',5':5,6]ピリド[2,3-b][1,4]オキサゼピン-9(6H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
4-(4-((9-(4-クロロフェニル)-3-メチル-3-アザスピロ[5.5]ウンデカ-8-エン-8-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
4-(4-((9-(4-クロロフェニル)-3-(1,3-ジフルオロプロパン-2-イル)-3-アザスピロ[5.5]ウンデカ-8-エン-8-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジフルオロ-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
4-(4-((5-(4-クロロフェニル)スピロ[2.5]オクタ-5-エン-6-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
4-(4-((7-(4-クロロフェニル)スピロ[3.5]ノナ-6-エン-6-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-3'-フルオロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-4-(4-((4,4-ジメチル-2-(ピリジン-3-イル)シクロヘキサ-1-エン-1-イル)メチル)ピペラジン-1-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
(R)-N-((4-(((1,4-ジオキサン-2-イル)メチル)アミノ)-3-フルオロ-5-ニトロフェニル)スルホニル)-4-(4-((6-(4-クロロフェニル)スピロ[3.5]ノナ-6-エン-7-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
(R)-N-((4-(((1,4-ジオキサン-2-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-4-(4-((6-(4-クロロフェニル)スピロ[3.5]ノナ-6-エン-7-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
(R)-N-((4-(((1,4-ジオキサン-2-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-4-(4-((6-(4-クロロフェニル)-2-オキサスピロ[3.5]ノナ-6-エン-7-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
(R)-N-((4-(((1,4-ジオキサン-2-イル)メチル)アミノ)-3-フルオロ-5-ニトロフェニル)スルホニル)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
4-(4-((6-(4-クロロフェニル)-2-オキサスピロ[3.5]ノナ-6-エン-7-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
4-(4-((6-(4-クロロフェニル)-2-オキサスピロ[3.5]ノナ-6-エン-7-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-(((4-フルオロテトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミド、
(S)-N-((4-(((1,4-ジオキサン-2-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-4-(4-((6-(4-クロロフェニル)スピロ[3.5]ノナ-6-エン-7-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-6-フルオロベンズアミド、
(S)-N-((4-(((1,4-ジオキサン-2-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-4-(4-((6-(4-クロロフェニル)スピロ[3.5]ノナ-6-エン-7-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-5-フルオロベンズアミド、
4-(4-((4'-クロロ-5,5-ビス(メチル-d3)-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)-2-メチルピペラジン-1-イル-2,3,3,5,5,6,6-d7)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
ジエチル((2-(((4-(N-(4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3'2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンゾイル)スルファモイル)-2-ニトロフェニル)アミノ)メチル)モルホリノ)メチル)ホスホネート、
ジエチル(((3-((4-(N-(4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンゾイル)スルファモイル)-2-ニトロフェニル)アミノ)プロピル)(メチル)アミノ)メチル)ホスホネート、
2-(((2-((4-(N-(4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンゾイル)スルファモイル)-2-ニトロフェニル)アミノ)エチル)((ピバロイルオキシ)メトキシ)ホスホリル)オキシ)エチルピバレート、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-(((1-メチル-1-オキシドホスフィナン-4-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-(((1-ヒドロキシ-1-オキシドホスフィナン-4-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミド、
((4-(((4-(N-(4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンゾイル)スルファモイル)-2-ニトロフェニル)アミノ)メチル)-1-オキシドホスフィナン-1-イル)オキシ)メチルピバレート、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-(((2-メチル-2-オキシド-1,3,2-オキサザホスフィナン-5-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-((2-(2-メチル-2-オキシド-1,3,2-オキサザホスフィナン-3-イル)エチル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミド、
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(7,8-dihydro-3H-imidazo[4',5':5,6]pyrido[2,3-b][1,4]oxazepin-9(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
4-(4-((9-(4-chlorophenyl)-3-methyl-3-azaspiro[5.5]undec-8-en-8-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
4-(4-((9-(4-chlorophenyl)-3-(1,3-difluoropropan-2-yl)-3-azaspiro[5.5]undec-8-en-8-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-difluoro-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
4-(4-((5-(4-chlorophenyl)spiro[2.5]oct-5-en-6-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
4-(4-((7-(4-chlorophenyl)spiro[3.5]nona-6-en-6-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-3'-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-4-(4-((4,4-dimethyl-2-(pyridin-3-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
(R)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-fluoro-5-nitrophenyl)sulfonyl)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
(R)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((6-(4-chlorophenyl)spiro[3.5]nona-6-en-7-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
(R)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((6-(4-chlorophenyl)-2-oxaspiro[3.5]nona-6-en-7-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
(R)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-fluoro-5-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
4-(4-((6-(4-chlorophenyl)-2-oxaspiro[3.5]nona-6-en-7-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
4-(4-((6-(4-chlorophenyl)-2-oxaspiro[3.5]nona-6-en-7-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,
(S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((6-(4-chlorophenyl)spiro[3.5]nona-6-en-7-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-6-fluorobenzamide,
(S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((6-(4-chlorophenyl)spiro[3.5]nona-6-en-7-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-5-fluorobenzamide,
4-(4-((4'-chloro-5,5-bis(methyl-d3)-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2-methylpiperazin-1-yl-2,3,3,5,5,6,6-d7)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
diethyl((2-(((4-(N-(4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3'2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzoyl)sulfamoyl)-2-nitrophenyl)amino)methyl)morpholino)methyl)phosphonate,
diethyl(((3-((4-(N-(4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzoyl)sulfamoyl)-2-nitrophenyl)amino)propyl)(methyl)amino)methyl)phosphonate,
2-(((2-((4-(N-(4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzoyl)sulfamoyl)-2-nitrophenyl)amino)ethyl)((pivaloyloxy)methoxy)phosphoryl)oxy)ethyl pivalate,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((1-methyl-1-oxidophosphinan-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((1-hydroxy-1-oxidophosphinan-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,
((4-(((4-(N-(4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzoyl)sulfamoyl)-2-nitrophenyl)amino)methyl)-1-oxidophosphinan-1-yl)oxy)methyl pivalate,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((2-methyl-2-oxido-1,3,2-oxazaphosphinan-5-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-((2-(2-methyl-2-oxido-1,3,2-oxazaphosphinan-3-yl)ethyl)amino)-3-nitrophenyl)sulfonyl)benzamide,
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-(((1-(ジメチルホスホリル)ピペリジン-4-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-(ジメチルホスホリル)-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
N-((4-(((1,4-ジオキサスピロ[4.5]デカン-8-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
N-((4-(((2-オキサスピロ[3.5]ノナン-7-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-((2-(ヘキサヒドロフロ[3,4-c]ピリジン-5(3H)-イル)エチル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミド、
(R)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-((2-(3-オキソオクタヒドロ-7H-イミダゾ[1,5-d][1,4]ジアゼピン-7-イル)エチル)アミノ)フェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-((2-(3-オキソオクタヒドロ-5H-ピロロ[3,4-c]ピリジン-5-イル)エチル)アミノ)フェニル)スルホニル)ベンズアミド、
N-((4-((2-(2-オキサ-5-アザビシクロ[2.2.2]オクタン-5-イル)エチル)アミノ)-3-ニトロフェニル)スルホニル)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-(((3-ヒドロキシ-3-メチルビシクロ[3.1.1]ヘプタン-6-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミド、
N-((4-((2-(2-オキサ-5-アザビシクロ[2.2.1]ヘプタン-5-イル)エチル)アミノ)-3-ニトロフェニル)スルホニル)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
2-((3R)-8-(2-((4-(N-(4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンゾイル)スルファモイル)-2-ニトロフェニル)アミノ)エチル)-6,6-ジフルオロ-8-アザビシクロ[3.2.1]オクタン-3-イル)酢酸、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-N-((4-((2-(6,6-ジフルオロ-8-アザビシクロ[3.2.1]オクタン-8-イル)エチル)アミノ)-3-ニトロフェニル)スルホニル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-((2-(テトラヒドロ-2H-ピラン-4-イル)-2-アザスピロ[3.3]ヘプタン-6-イル)アミノ)フェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-チオピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-(((1-イミノ-1-オキシドヘキサヒドロ-1l6-チオピラン-4-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-(((4-(メチルスルホニル)モルホリン-2-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-(((4-((ジメチル(オキソ)-λ6-スルファネイリデン)アミノ)シクロヘキシル)メチル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-((2-(4-((ジメチル(オキソ)-λ6-スルファネイリデン)アミノ)ピペリジン-1-イル)エチル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミド、
N-((4-(((4-アミノテトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-((1-(テトラヒドロ-2H-ピラン-4-イル)シクロプロピル)アミノ)フェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-((2-(5,6-ジヒドロイミダゾ[1,2-a]ピラジン-7(8H)-イル)エチル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン-6-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-N-((4-((3-(ジフルオロメトキシ)ベンジル)アミノ)-3-ニトロフェニル)スルホニル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((3,4,5-トリヒドロキシテトラヒドロフラン-2-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((3,4,5,6-テトラヒドロキシテトラヒドロ-2H-ピラン-2-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-(((4,5-ジヒドロキシ-6,6-ジメチルテトラヒドロ-2H-ピラン-2-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミド、
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((1-(dimethylphosphoryl)piperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-(dimethylphosphoryl)-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
N-((4-(((1,4-dioxaspiro[4.5]decan-8-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
N-((4-(((2-oxaspiro[3.5]nonan-7-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-((2-(hexahydrofuro[3,4-c]pyridin-5(3H)-yl)ethyl)amino)-3-nitrophenyl)sulfonyl)benzamide,
(R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-((2-(3-oxoocthydro-7H-imidazo[1,5-d][1,4]diazepin-7-yl)ethyl)amino)phenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-((2-(3-oxooctahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)ethyl)amino)phenyl)sulfonyl)benzamide,
N-((4-((2-(2-oxa-5-azabicyclo[2.2.2]octan-5-yl)ethyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((3-hydroxy-3-methylbicyclo[3.1.1]heptan-6-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,
N-((4-((2-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
2-((3R)-8-(2-((4-(N-(4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzoyl)sulfamoyl)-2-nitrophenyl)amino)ethyl)-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl)acetic acid,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((2-(6,6-difluoro-8-azabicyclo[3.2.1]octan-8-yl)ethyl)amino)-3-nitrophenyl)sulfonyl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-((2-(tetrahydro-2H-pyran-4-yl)-2-azaspiro[3.3]heptan-6-yl)amino)phenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-thiopyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((1-imino-1-oxidohexahydro-116-thiopyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((4-(methylsulfonyl)morpholin-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((4-((dimethyl(oxo)-lambda6-sulfaneilidene)amino)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-((2-(4-((dimethyl(oxo)-lambda6-sulfaneilidene)amino)piperidin-1-yl)ethyl)amino)-3-nitrophenyl)sulfonyl)benzamide,
N-((4-(((4-aminotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-((1-(tetrahydro-2H-pyran-4-yl)cyclopropyl)amino)phenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-((2-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)ethyl)amino)-3-nitrophenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-6-yl)methyl)amino)phenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(difluoromethoxy)benzyl)amino)-3-nitrophenyl)sulfonyl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((3,4,5-trihydroxytetrahydrofuran-2-yl)methyl)amino)phenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl)amino)phenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((4,5-dihydroxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((2,3,5-トリヒドロキシ-6-(ヒドロキシメチル)テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((2,3,4,5,6-ペンタヒドロキシシクロヘキシル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
(R)-N-((4-(((1,4-ジオキサン-2-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-4-(1-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)-1,2,3,6-テトラヒドロピリジン-4-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
4-(1-((6-(4-クロロフェニル)スピロ[3.5]ノナ-6-エン-7-イル)メチル)-1,2,3,6-テトラヒドロピリジン-4-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
(S)-N-((4-(((1,4-ジオキサン-2-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-5-(4-((6-(4-クロロフェニル)スピロ[3.5]ノナ-6-エン-7-イル)メチル)ピペラジン-1-イル)-3-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ピコリンアミド、
(S)-N-((4-(((1,4-ジオキサン-2-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-6-(4-((6-(4-クロロフェニル)スピロ[3.5]ノナ-6-エン-7-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ニコチンアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-(((4-フルオロテトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミド、
(S)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-(((2-フルオロ-1,4-ジオキサン-2-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミド、
(R)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-(((2-フルオロ-1,4-ジオキサン-2-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミド、
(S)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-N-((4-(((4-フルオロテトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-2-(4-メチル-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-N-((4-((((R)-2-フルオロ-1,4-ジオキサン-2-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-2-((S)-4-メチル-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-N-((4-((((S)-2-フルオロ-1,4-ジオキサン-2-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-2-((S)-4-メチル-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
(R)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-N-((4-(((4-フルオロテトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-2-(4-メチル-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-N-((4-((((R)-2-フルオロ-1,4-ジオキサン-2-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-2-((R)-4-メチル-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-N-((4-((((S)-2-フルオロ-1,4-ジオキサン-2-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-2-((R)-4-メチル-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
(R)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(4,4-ジフルオロ-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-(((2-フルオロ-1,4-ジオキサン-2-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミド、
(S)-N-((4-(((1,4-ジオキサン-2-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(4,4-ジフルオロ-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(4,4-ジフルオロ-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-(((4-フルオロテトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(4,4-ジメチル-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)-2-(3-(トリフルオロメチル)-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
(R)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)-2-(4-(トリフルオロメチル)-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
(S)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)-2-(3-(トリフルオロメチル)-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
(R)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3-シアノ-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
(S)-2-(3-アミノ-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
(S)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3-メトキシ-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((2,3,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((2,3,4,5,6-pentahydroxycyclohexyl)methyl)amino)phenyl)sulfonyl)benzamide,
(R)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(1-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
4-(1-((6-(4-chlorophenyl)spiro[3.5]nona-6-en-7-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
(S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-5-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-3-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)picolinamide,
(S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)nicotinamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,
(S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((2-fluoro-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,
(R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((2-fluoro-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,
(S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(4-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((R)-2-fluoro-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((S)-4-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((S)-2-fluoro-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((S)-4-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
(R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(4-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((R)-2-fluoro-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((R)-4-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((S)-2-fluoro-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((R)-4-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
(R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4,4-difluoro-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((2-fluoro-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,
(S)-N-((4-((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4,4-difluoro-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4,4-difluoro-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4,4-dimethyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2-(3-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
(R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2-(4-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
(S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2-(3-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
(R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-cyano-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
(S)-2-(3-amino-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
(S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methoxy-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
(S)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3-メチル-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
(R)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3-ヒドロキシ-3-メチル-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
(R)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3-メチル-3-(トリフルオロメチル)-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
(S)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3-シアノ-3-メチル-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
(S)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(2-メチル-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
(R)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)-2-(2-(トリフルオロメチル)-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(5,5-ジオキシド-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]チアゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)-2-(4-(トリフルオロメチル)-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]チアゼピン-1(7H)-イル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3-メトキシ-3-メチル-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]チアゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3-メチル-3-(トリフルオロメチル)-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]チアゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,3-ジフルオロ-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-(((4-フルオロテトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミド、
(R)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3-シアノ-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-(((4-フルオロテトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミド、
(S)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-N-((4-(((4-フルオロテトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-2-(3-ヒドロキシ-3-メチル-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
(S)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-N-((4-(((4-フルオロテトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-2-(3-メチル-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,3-ジメチル-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-(((4-フルオロテトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミド、
(S)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-N-((4-(((4-フルオロテトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-2-(2-メチル-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
(R)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-N-((4-(((4-フルオロテトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-2-(3-(ヒドロキシメチル)-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)-2-(2'H,4'H-スピロ[シクロブタン-1,3'-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン]-1'(7'H)-イル)ベンズアミド、
(S)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,3-ジメチル-4-(トリフルオロメチル)-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
(R)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3-(ヒドロキシメチル)-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)-2-(9-オキソ-6,7,8,9-テトラヒドロピロロ[3',2':5,6]ピリド[3,2-b]アゼピン-5(1H)-イル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)-2-(5-(オキセタン-3-イル)-3,4,5,7-テトラヒドロピロロ[3',2':5,6]ピリド[2,3-b][1,4]ジアゼピン-1(2H)-イル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)-2-(2-オキソ-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(5-イミノ-5-オキシド-3,4,5,7-テトラヒドロ-5l4-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]チアゼピン-1(2H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(5-メチル-5-オキシド-3,4,7-トリヒドロピロロ[3',2':5,6]ピリド[3,2-b][1,4]アザホスフェピン-1(2H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
(S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
(R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-hydroxy-3-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
(R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methyl-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
(S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-cyano-3-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
(S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
(R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2-(2-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(5,5-dioxido-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]thiazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2-(4-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]thiazepin-1(7H)-yl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methoxy-3-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]thiazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methyl-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]thiazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,3-difluoro-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,
(R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-cyano-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,
(S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(3-hydroxy-3-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
(S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(3-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,3-dimethyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,
(S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(2-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
(R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(3-(hydroxymethyl)-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2-(2'H,4'H-spiro[cyclobutane-1,3'-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine]-1'(7'H)-yl)benzamide,
(S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,3-dimethyl-4-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
(R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-(hydroxymethyl)-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2-(9-oxo-6,7,8,9-tetrahydropyrrolo[3',2':5,6]pyrido[3,2-b]azepin-5(1H)-yl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2-(5-(oxetan-3-yl)-3,4,5,7-tetrahydropyrrolo[3',2':5,6]pyrido[2,3-b][1,4]diazepin-1(2H)-yl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2-(2-oxo-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(5-imino-5-oxido-3,4,5,7-tetrahydro-514-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]thiazepin-1(2H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(5-methyl-5-oxido-3,4,7-trihydropyrrolo[3',2':5,6]pyrido[3,2-b][1,4]azaphosphepin-1(2H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-(((3-フルオロテトラヒドロ-2H-ピラン-3-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-((3-モルホリノプロピル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミド、
(S)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-(((4-メチルモルホリン-2-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミド、
(S)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((4-(オキセタン-3-イル)モルホリン-2-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-(((4-ヒドロキシ-4-メチルシクロヘキシル)メチル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-((((1s,4s)-4-メトキシシクロヘキシル)メチル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-((((1r,4r)-4-ヒドロキシ-4-メチルシクロヘキシル)メチル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-((((1r,4r)-4-エチル-4-ヒドロキシシクロヘキシル)メチル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-((1-(オキセタン-3-イル)ピペリジン-4-イル)アミノ)フェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-(((1r,4r)-4-モルホリノシクロヘキシル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-((4-(メチル(オキセタン-3-イル)アミノ)シクロヘキシル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((1,4,4-トリフルオロシクロヘキシル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-((4-フルオロテトラヒドロ-2H-ピラン-4-イル)メトキシ)-3-ニトロフェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-((3-フルオロテトラヒドロ-2H-ピラン-3-イル)メトキシ)-3-ニトロフェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-(3-モルホリノプロポキシ)-3-ニトロフェニル)スルホニル)ベンズアミド、
(R)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-((4-メチルモルホリン-2-イル)メトキシ)-3-ニトロフェニル)スルホニル)ベンズアミド、
(R)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-((4-(オキセタン-3-イル)モルホリン-2-イル)メトキシ)フェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-((4-ヒドロキシ-4-メチルシクロヘキシル)メトキシ)-3-ニトロフェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-(((1s,4s)-4-メトキシシクロヘキシル)メトキシ)-3-ニトロフェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-(((1r,4r)-4-ヒドロキシ-4-メチルシクロヘキシル)メトキシ)-3-ニトロフェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-(((1r,4r)-4-エチル-4-ヒドロキシシクロヘキシル)メトキシ)-3-ニトロフェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-((1-(オキセタン-3-イル)ピペリジン-4-イル)オキシ)フェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-(((1r,4r)-4-モルホリノシクロヘキシル)オキシ)-3-ニトロフェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-((4-(メチル(オキセタン-3-イル)アミノ)シクロヘキシル)オキシ)-3-ニトロフェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-((1,4,4-トリフルオロシクロヘキシル)メトキシ)フェニル)スルホニル)ベンズアミド、
4-(4-((4-(4-クロロフェニル)-5,6-ジヒドロ-2H-ピラン-3-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((3-fluorotetrahydro-2H-pyran-3-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-((3-morpholinopropyl)amino)-3-nitrophenyl)sulfonyl)benzamide,
(S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((4-methylmorpholin-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,
(S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((4-(oxetan-3-yl)morpholin-2-yl)methyl)amino)phenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((1s,4s)-4-methoxycyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-((((1r,4r)-4-ethyl-4-hydroxycyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-((1-(oxetan-3-yl)piperidin-4-yl)amino)phenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((1r,4r)-4-morpholinocyclohexyl)amino)-3-nitrophenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-((4-(methyl(oxetan-3-yl)amino)cyclohexyl)amino)-3-nitrophenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((1,4,4-trifluorocyclohexyl)methyl)amino)phenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)-3-nitrophenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-((3-fluorotetrahydro-2H-pyran-3-yl)methoxy)-3-nitrophenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(3-morpholinopropoxy)-3-nitrophenyl)sulfonyl)benzamide,
(R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-((4-methylmorpholin-2-yl)methoxy)-3-nitrophenyl)sulfonyl)benzamide,
(R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-((4-(oxetan-3-yl)morpholin-2-yl)methoxy)phenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-((4-hydroxy-4-methylcyclohexyl)methoxy)-3-nitrophenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((1s,4s)-4-methoxycyclohexyl)methoxy)-3-nitrophenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)methoxy)-3-nitrophenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((1r,4r)-4-ethyl-4-hydroxycyclohexyl)methoxy)-3-nitrophenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-((1-(oxetan-3-yl)piperidin-4-yl)oxy)phenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((1r,4r)-4-morpholinocyclohexyl)oxy)-3-nitrophenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-((4-(methyl(oxetan-3-yl)amino)cyclohexyl)oxy)-3-nitrophenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-((1,4,4-trifluorocyclohexyl)methoxy)phenyl)sulfonyl)benzamide,
4-(4-((4-(4-chlorophenyl)-5,6-dihydro-2H-pyran-3-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
(Z)-4-(4-((2-(4-クロロフェニル)シクロオクタ-1-エン-1-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-4-メトキシ-4-メチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
4-(5-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)-2,5-ジアザビシクロ[2.2.2]オクタン-2-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-(3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニルスルホンイミドイル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-N-((5-クロロ-6-((テトラヒドロ-2H-ピラン-4-イル)メトキシ)ピリジン-3-イル)スルホニル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)-3-(S-(トリフルオロメチル)スルホンイミドイル)フェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-[1,4]オキサゼピノ[3,2-f]インドール-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
4-(4-((9-(4-クロロフェニル)-3-イソプロピル-3-アザスピロ[5.5]ウンデカ-8-エン-8-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
4-(4-((9-(4-クロロフェニル)-3-(オキセタン-3-イル)-3-アザスピロ[5.5]ウンデカ-8-エン-8-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ビス(フルオロメチル)-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
4-(4-(1-(4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)シクロプロピル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
4-(4-((6-(4-クロロフェニル)スピロ[2.5]オクタ-5-エン-5-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-3',5,5-トリメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
4-(4-((2-(1H-インドール-5-イル)-4,4-ジメチルシクロヘキサ-1-エン-1-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
(S)-N-((4-(((1,4-ジオキサン-2-イル)メチル)アミノ)-3-フルオロ-5-ニトロフェニル)スルホニル)-4-(4-((6-(4-クロロフェニル)スピロ[3.5]ノナ-6-エン-7-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
(S)-N-((4-(((1,4-ジオキサン-2-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-4-(4-((6-(4-クロロフェニル)スピロ[3.5]ノナ-6-エン-7-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
(S)-N-((4-(((1,4-ジオキサン-2-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-4-(4-((6-(4-クロロフェニル)-2-オキサスピロ[3.5]ノナ-6-エン-7-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
(S)-N-((4-(((1,4-ジオキサン-2-イル)メチル)アミノ)-3-フルオロ-5-ニトロフェニル)スルホニル)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
4-(4-((6-(4-クロロフェニル)スピロ[3.5]ノナ-6-エン-7-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
4-(4-((6-(4-クロロフェニル)スピロ[3.5]ノナ-6-エン-7-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-(((4-フルオロテトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミド
(S)-N-((4-(((1,4-ジオキサン-2-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-4-(4-((6-(4-クロロフェニル)スピロ[3.5]ノナ-6-エン-7-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-3-フルオロベンズアミド、
(S)-N-((4-(((1,4-ジオキサン-2-イル)メチル)アミノ)-3-フルオロ-5-ニトロフェニル)スルホニル)-4-(4-((6-(4-クロロフェニル)スピロ[3.5]ノナ-6-エン-7-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-6-フルオロベンズアミド、
4-(4-((4'-クロロ-5,5-ビス(メチル-d3)-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル-2,2,3,3,4,4-d6)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
((2-(((4-(N-(4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンゾイル)スルファモイル)-2-ニトロフェニル)アミノ)メチル)モルホリノ)メチル)ホスホン酸、
ジエチル(2-((2-((4-(N-(4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3'2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンゾイル)スルファモイル)-2-ニトロフェニル)アミノ)エチル)(メチル)アミノ)エチル)ホスホネート、
(Z)-4-(4-((2-(4-chlorophenyl)cyclooct-1-en-1-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-4-methoxy-4-methyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
4-(5-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2,5-diazabicyclo[2.2.2]octan-2-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-(3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenylsulfonimidoyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((5-chloro-6-((tetrahydro-2H-pyran-4-yl)methoxy)pyridin-3-yl)sulfonyl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-3-(S-(trifluoromethyl)sulfonimidoyl)phenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-[1,4]oxazepino[3,2-f]indol-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
4-(4-((9-(4-chlorophenyl)-3-isopropyl-3-azaspiro[5.5]undec-8-en-8-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
4-(4-((9-(4-chlorophenyl)-3-(oxetan-3-yl)-3-azaspiro[5.5]undec-8-en-8-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-bis(fluoromethyl)-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
4-(4-(1-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)cyclopropyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
4-(4-((6-(4-chlorophenyl)spiro[2.5]oct-5-en-5-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-3',5,5-trimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
4-(4-((2-(1H-indol-5-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
(S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-fluoro-5-nitrophenyl)sulfonyl)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
(S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
(S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((6-(4-chlorophenyl)-2-oxaspiro[3.5]nona-6-en-7-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
(S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-fluoro-5-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
4-(4-((6-(4-chlorophenyl)spiro[3.5]nona-6-en-7-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
4-(4-((6-(4-chlorophenyl)spiro[3.5]nona-6-en-7-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide
(S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-3-fluorobenzamide,
(S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-fluoro-5-nitrophenyl)sulfonyl)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-6-fluorobenzamide,
4-(4-((4'-chloro-5,5-bis(methyl-d3)-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl-2,2,3,3,4,4-d6)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
((2-(((4-(N-(4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzoyl)sulfamoyl)-2-nitrophenyl)amino)methyl)morpholino)methyl)phosphonic acid,
diethyl(2-((2-((4-(N-(4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3'2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzoyl)sulfamoyl)-2-nitrophenyl)amino)ethyl)(methyl)amino)ethyl)phosphonate,
エチルP-(2-((4-(N-(4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3'2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンゾイル)スルファモイル)-2-ニトロフェニル)アミノ)エチル)-N,N-ジメチルホスホンアミデート、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-(((1-(ジメチルアミノ)-1-オキシドホスフィナン-4-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-(((1-エトキシ-1-オキシドホスフィナン-4-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-(((1-イソプロポキシ-1-オキシドホスフィナン-4-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((1,2,3-トリメチル-2-オキシド-1,3,2-ジアザホスフィナン-5-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-((2-(2-メチル-2-オキシド-1,3,2-ジアザホスフィナン-1-イル)エチル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-(((4-(ジメチルホスホリル)モルホリン-2-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-(ジメチルホスホリル)-3-ニトロフェニル)スルホニル)ベンズアミド、
N-((4-(((1,4-ジチアスピロ[4.5]デカン-8-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
N-((4-((2-(6-アザスピロ[2.5]オクタン-6-イル)エチル)アミノ)-3-ニトロフェニル)スルホニル)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-N-((4-((2-(2,2-ジフルオロ-7-アザスピロ[3.5]ノナン-7-イル)エチル)アミノ)-3-ニトロフェニル)スルホニル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-((2-(2-(オキセタン-3-イル)オクタヒドロ-5H-ピロロ[3,4-c]ピリジン-5-イル)エチル)アミノ)フェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-((2-(1-オキソオクタヒドロ-5H-ピロロ[3,4-c]ピリジン-5-イル)エチル)アミノ)フェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-(((3-ヒドロキシビシクロ[3.1.1]ヘプタン-6-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミド、
N-((4-(((3-アミノ-3-メチルビシクロ[3.1.1]ヘプタン-6-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-((2-(5-(オキセタン-3-イル)-2,5-ジアザビシクロ[2.2.1]ヘプタン-2-イル)エチル)アミノ)フェニル)スルホニル)ベンズアミド、
2-((3S)-8-(2-((4-(N-(4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンゾイル)スルファモイル)-2-ニトロフェニル)アミノ)エチル)-6,6-ジフルオロ-8-アザビシクロ[3.2.1]オクタン-3-イル)酢酸、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-N-((4-((2-(6,6-ジフルオロ-8-アザビシクロ[3.2.1]オクタン-8-イル)エチル)アミノ)-3-ニトロフェニル)スルホニル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
N-((4-((7-オキサスピロ[3.5]ノナン-2-イル)アミノ)-3-ニトロフェニル)スルホニル)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-(((1,1-ジオキシドテトラヒドロ-2H-チオピラン-4-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-(((1-(イソプロピルイミノ)-1-オキシドヘキサヒドロ-1λ6-チオピラン-4-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-(((4-(S-メチルスルホンイミドイル)モルホリン-2-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((4-((1-オキシドテトラヒドロ-1λ6-チオフェン-1-イリデン)アミノ)シクロヘキシル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
(S)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-((1-(4-((ジメチル(オキソ)-λ6-スルファネイリデン)アミノ)ピペリジン-1-イル)プロパン-2-イル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-N-((4-(((4-シアノテトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-((2-(テトラヒドロ-2H-ピラン-4-イル)プロパン-2-イル)アミノ)フェニル)スルホニル)ベンズアミド、
Ethyl P-(2-((4-(N-(4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3'2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzoyl)sulfamoyl)-2-nitrophenyl)amino)ethyl)-N,N-dimethylphosphonamidate,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((1-(dimethylamino)-1-oxidophosphinan-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((1-ethoxy-1-oxidophosphinan-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((1-isopropoxy-1-oxidophosphinan-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((1,2,3-trimethyl-2-oxide-1,3,2-diazaphosphinan-5-yl)methyl)amino)phenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-((2-(2-methyl-2-oxido-1,3,2-diazaphosphinan-1-yl)ethyl)amino)-3-nitrophenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((4-(dimethylphosphoryl)morpholin-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(dimethylphosphoryl)-3-nitrophenyl)sulfonyl)benzamide,
N-((4-(((1,4-dithiaspiro[4.5]decan-8-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
N-((4-((2-(6-azaspiro[2.5]octan-6-yl)ethyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((2-(2,2-difluoro-7-azaspiro[3.5]nonan-7-yl)ethyl)amino)-3-nitrophenyl)sulfonyl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-((2-(2-(oxetan-3-yl)octahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)ethyl)amino)phenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-((2-(1-oxooctahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)ethyl)amino)phenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((3-hydroxybicyclo[3.1.1]heptan-6-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,
N-((4-(((3-amino-3-methylbicyclo[3.1.1]heptan-6-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-((2-(5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)ethyl)amino)phenyl)sulfonyl)benzamide,
2-((3S)-8-(2-((4-(N-(4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzoyl)sulfamoyl)-2-nitrophenyl)amino)ethyl)-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl)acetic acid,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((2-(6,6-difluoro-8-azabicyclo[3.2.1]octan-8-yl)ethyl)amino)-3-nitrophenyl)sulfonyl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
N-((4-((7-oxaspiro[3.5]nonan-2-yl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((1-(isopropylimino)-1-oxidohexahydro-1λ6-thiopyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((4-(S-methylsulfonimidoyl)morpholin-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((4-((1-oxidotetrahydro-1λ6-thiophen-1-ylidene)amino)cyclohexyl)methyl)amino)phenyl)sulfonyl)benzamide,
(S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-((1-(4-((dimethyl(oxo)-lambda6-sulfaneilidene)amino)piperidin-1-yl)propan-2-yl)amino)-3-nitrophenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-cyanotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-((2-(tetrahydro-2H-pyran-4-yl)propan-2-yl)amino)phenyl)sulfonyl)benzamide,
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-((2-(5,6-ジヒドロ-[1,2,4]トリアゾロ[1,5-a]ピラジン-7(8H)-イル)エチル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((1-(チアゾール-2-イル)ピペリジン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-N-((4-((4-(ジフルオロメトキシ)ベンジル)アミノ)-3-ニトロフェニル)スルホニル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-(((3,5-ジヒドロキシテトラヒドロフラン-2-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((3,4,5-トリヒドロキシ-6,6-ジメチルテトラヒドロ-2H-ピラン-2-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((2,3,5-トリヒドロキシテトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((3,4,5-トリヒドロキシ-6-(メチルチオ)テトラヒドロ-2H-ピラン-2-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((3,4,5-トリヒドロキシ-6-(((4,5,6-トリヒドロキシ-2-(ヒドロキシメチル)テトラヒドロ-2H-ピラン-3-イル)メトキシ)メチル)テトラヒドロ-2H-ピラン-2-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
N-((4-(((1,4-ジオキサン-2-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-4-(1-((6-(4-クロロフェニル)-2-オキサスピロ[3.5]ノナ-6-エン-7-イル)メチル)-1,2,3,6-テトラヒドロピリジン-4-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
4-(1-((6-(4-クロロフェニル)-2-オキサスピロ[3.5]ノナ-6-エン-7-イル)メチル)-1,2,3,6-テトラヒドロピリジン-4-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
(S)-6-(4-((6-(4-クロロフェニル)-2-オキサスピロ[3.5]ノナ-6-エン-7-イル)メチル)ピペラジン-1-イル)-4-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-3-イル)メチル)アミノ)フェニル)スルホニル)ニコチンアミド、又は
(S)-N-((4-(((1,4-ジオキサン-2-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-6-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ニコチンアミド
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-((2-(5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)ethyl)amino)-3-nitrophenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((1-(thiazol-2-yl)piperidin-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((4-(difluoromethoxy)benzyl)amino)-3-nitrophenyl)sulfonyl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((3,5-dihydroxytetrahydrofuran-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((3,4,5-trihydroxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)methyl)amino)phenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((2,3,5-trihydroxytetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((3,4,5-trihydroxy-6-(methylthio)tetrahydro-2H-pyran-2-yl)methyl)amino)phenyl)sulfonyl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((3,4,5-trihydroxy-6-(((4,5,6-trihydroxy-2-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)methoxy)methyl)tetrahydro-2H-pyran-2-yl)methyl)amino)phenyl)sulfonyl)benzamide,
N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(1-((6-(4-chlorophenyl)-2-oxaspiro[3.5]non-6-en-7-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
4-(1-((6-(4-chlorophenyl)-2-oxaspiro[3.5]nona-6-en-7-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
(S)-6-(4-((6-(4-chlorophenyl)-2-oxaspiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-4-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-3-yl)methyl)amino)phenyl)sulfonyl)nicotinamide, or
(S)-N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)nicotinamide
本発明の化合物は1つ以上の不斉炭素原子を含有していてもよい。したがって、化合物は、ジアステレオマー、エナンチオマー、又はそれらの混合物として存在していてもよい。化合物の合成は、ラセミ体、ジアステレオマー、又はエナンチオマーを、出発物質として又は中間体として採用してもよい。ジアステレオマー化合物は、クロマトグラフ法又は結晶化法により分離されてもよい。同様に、エナンチオマー混合物は、同じ技術又は当技術分野において公知のその他の技術を使用して分離されてもよい。不斉炭素原子の各々は、R又はS配置であってもよく、これらの配置は共に本発明の範囲内である。 The compounds of the present invention may contain one or more asymmetric carbon atoms. Thus, the compounds may exist as diastereomers, enantiomers, or mixtures thereof. The synthesis of the compounds may employ racemates, diastereomers, or enantiomers as starting materials or as intermediates. Diastereomeric compounds may be separated by chromatographic or crystallization techniques. Similarly, enantiomeric mixtures may be separated using the same techniques or other techniques known in the art. Each of the asymmetric carbon atoms may be in the R or S configuration, both of which are within the scope of the present invention.
1つ以上のキラル中心を有する化合物は、様々な立体異性形態で存在することができる。立体異性体は、これらの空間的配置のみが異なる化合物である。立体異性体はすべてのジアステレオマー、エナンチオマー、及びエピマー形態並びにラセミ体及びそれらの混合物を含む。 Compounds with one or more chiral centers can exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial arrangement. Stereoisomers include all diastereomeric, enantiomeric, and epimeric forms as well as racemates and mixtures thereof.
「幾何異性体」という用語は、2つの置換基が両方とも環(cis)の同じ側にあるか、置換基が各々環(trans)の反対側にある少なくとも2つの置換基を有する環式化合物を指す。開示化合物が命名されている、又は立体化学が示されずに構造により示されている場合、名称又は構造は、可能な立体異性体、又は幾何異性体の1つ以上、又は包含された立体異性体又は幾何異性体の混合物を包含すると理解されている。 The term "geometric isomer" refers to a cyclic compound having at least two substituents, where the two substituents are both on the same side of the ring (cis) or the substituents are each on opposite sides of the ring (trans). When a disclosed compound is named or illustrated by a structure without indicating stereochemistry, the name or structure is understood to encompass one or more of the possible stereoisomers, or geometric isomers, or a mixture of the encompassed stereoisomers or geometric isomers.
幾何異性体が名称又は構造で示されている場合、命名又は示されている異性体は、別の異性体より高い度合で存在すること、つまり命名又は示されている幾何異性体の幾何異性体純度は50%より高い、例えば、少なくとも60重量%、70重量%、80重量%、90重量%、99重量%、又は99.9重量%の純度であることを理解されたい。幾何異性体純度は、混合物中の命名又は示されている幾何異性体の重量を、混合物中のすべての幾何異性体の総重量で割ることにより決定される。 When a geometric isomer is designated by name or structure, it is understood that the named or designated isomer is present to a greater degree than another isomer, i.e., the geometric isomer purity of the named or designated geometric isomer is greater than 50%, e.g., at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight pure. Geometric isomer purity is determined by dividing the weight of the named or designated geometric isomer in the mixture by the total weight of all geometric isomers in the mixture.
ラセミ混合物は、1つのエナンチオマーが50%及びその対応するエナンチオマーが50%であることを意味する。キラル中心の立体化学が示されずに、1つのキラル中心を有する化合物が命名又は示されている場合、名称又は構造は、化合物の両方の可能なエナンチオマー形態(例えば、エナンチオマー的に純粋なもの、エナンチオマー的に富化されたものの両方又はラセミ)を包含すると理解される。キラル中心の立体化学が示されずに、2つ又はそれよりも多くのキラル中心を有する化合物が命名又は示されている場合、名称又は構造は、化合物のすべての可能なジアステレオマー形態(例えば、ジアステレオマー的に純粋なもの、ジアステレオマーが富化されたもの)及び1つ以上のジアステレオマーの等モル混合物(例えば、ラセミ混合物)を包含すると理解される。 A racemic mixture means 50% of one enantiomer and 50% of its corresponding enantiomer. When a compound with one chiral center is named or shown without indicating the stereochemistry of the chiral center, the name or structure is understood to encompass both possible enantiomeric forms of the compound (e.g., both enantiomerically pure, enantiomerically enriched, or racemic). When a compound with two or more chiral centers is named or shown without indicating the stereochemistry of the chiral center, the name or structure is understood to encompass all possible diastereomeric forms of the compound (e.g., diastereomerically pure, diastereomerically enriched) and equimolar mixtures of one or more diastereomers (e.g., racemic mixtures).
エナンチオマー及びジアステレオマー混合物は、周知の方法、例えば、キラル相ガスクロマトグラフィー、キラル相高速液体クロマトグラフィー、キラル塩複合体としての化合物の結晶化、又はキラル溶媒中での化合物の結晶化により、これらの構成成分エナンチオマー又は立体異性体へと分解することができる。エナンチオマー及びジアステレオマーはまた、周知の非対称的合成法により、ジアステレオマー的に又はエナンチオマー的に純粋な中間体、試薬、及び触媒から得ることができる。 Enantiomeric and diastereomeric mixtures can be resolved into their component enantiomers or stereoisomers by well-known methods, such as chiral-phase gas chromatography, chiral-phase high-performance liquid chromatography, crystallization of the compound as a chiral salt complex, or crystallization of the compound in a chiral solvent. Enantiomers and diastereomers can also be obtained from diastereomerically- or enantiomerically-pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.
化合物が、単一のエナンチオマーを示す名称又は構造により指定されている場合、別段の指示がない限り、化合物は少なくとも60%、70%、80%、90%、99%又は99.9%光学的に純粋である(「エナンチオマー的に純粋」とも呼ばれる)。光学純度は、混合物中の両エナンチオマーの総重量で割った、混合物中の命名又は示されているエナンチオマーの重量である。 If a compound is designated by a name or structure indicating a single enantiomer, unless otherwise indicated, the compound is at least 60%, 70%, 80%, 90%, 99% or 99.9% optically pure (also called "enantiomerically pure"). Optical purity is the weight of the named or shown enantiomer in a mixture divided by the total weight of both enantiomers in the mixture.
開示化合物の立体化学が構造により命名又は示されている、及び命名又は示されている構造が1つより多くの立体異性体(例えば、ジアステレオマー対の場合のように)を包含する場合、包含された立体異性体の1つ又は包含された立体異性体の任意の混合物が含まれると理解されたい。命名又は示されている立体異性体の立体異性純度が少なくとも60重量%、70重量%、80重量%、90重量%、99重量%又は99.9重量%であることをさらに理解されたい。この場合、立体異性純度は、名称又は構造により包含される立体異性体の混合物中の総重量を、すべての立体異性体の混合物中の総重量で割ることにより決定される。 Where the stereochemistry of a disclosed compound is named or depicted by structure, and the named or depicted structure encompasses more than one stereoisomer (e.g., as in the case of a diastereomeric pair), it is understood that one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers is included. It is further understood that the stereoisomeric purity of the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight. In this case, stereoisomeric purity is determined by dividing the total weight in the mixture of the stereoisomers encompassed by the name or structure by the total weight in the mixture of all stereoisomers.
非修飾化合物と比較して改善された(例えば、向上した、より高い)医薬溶解性、安定性、バイオアベイラビリティ、及び/又は治療指数を有する修飾を含む、そのような化合物のいずれか1つの修飾化合物も考えられる。修飾物の例としては、限定はされないが、プロドラッグ誘導体、及び重水素富化化合物が挙げられる。例えば:
・ プロドラッグ誘導体:対象に投与されるとインビボで本発明の活性化合物へ転化する、プロドラッグ[Nature Reviews of Drug Discovery、2008年、7巻、255頁]。多くの事例において、プロドラッグ自体も本発明による化合物の範囲内に含まれることに注意する。本発明の化合物のプロドラッグは、標準的な有機反応により、例えば、カルバミル化剤(例えば、1,1-アシルオキシアルキルカルボノクロリデート、パラニトロフェニルカーボネートなど)又はアシル化剤と反応させることにより、調製できる。プロドラッグを作製する方法及び方策のさらなる例は、Bioorganic and Medicinal Chemistry Letters、1994年、4巻、1985頁に記載されている。
・ 重水素富化化合物:重水素(D又は2H)は水素の安定な非放射性同位体であり、原子量が2.0144である。水素は、同位体XH(水素又はプロチウム)、D(2H又は重水素)、及びT(3H又はトリチウム)の混合物として天然に存在する。重水素の天然存在度は0.015%である。当業者は、H原子を有するあらゆる化合物において、H原子が実際にはH及びDの混合物を表し、約0.015%がDであることを認識している。したがって、その天然存在度である0.015%を超えるように富化された重水素のレベルを有する化合物は、非天然であり、その結果として、それらの富化されていない対応物よりも新規性があると考えるべきである。
Modified compounds of any one of such compounds are also contemplated, including modifications that have improved (e.g., enhanced, higher) pharmaceutical solubility, stability, bioavailability, and/or therapeutic index compared to the unmodified compound. Examples of modifications include, but are not limited to, prodrug derivatives, and deuterium-enriched compounds. For example:
Prodrug derivatives: Prodrugs that are converted to the active compounds of the present invention in vivo when administered to a subject [Nature Reviews of Drug Discovery, 2008, vol. 7, p. 255]. It is noted that in many cases, prodrugs themselves are also included within the scope of the compounds according to the present invention. Prodrugs of the compounds of the present invention can be prepared by standard organic reactions, for example, by reacting with a carbamylating agent (e.g., 1,1-acyloxyalkylcarbonochloridate, paranitrophenyl carbonate, etc.) or an acylating agent. Further examples of methods and strategies for making prodrugs are described in Bioorganic and Medicinal Chemistry Letters, 1994, vol. 4, p. 1985.
Deuterium-enriched compounds: Deuterium (D or 2 H) is a stable, non-radioactive isotope of hydrogen with an atomic weight of 2.0144. Hydrogen occurs naturally as a mixture of the isotopes XH (hydrogen or protium), D ( 2H or deuterium), and T ( 3H or tritium). The natural abundance of deuterium is 0.015%. Those skilled in the art recognize that in any compound with an H atom, the H atom actually represents a mixture of H and D, with approximately 0.015% being D. Thus, compounds with a level of deuterium enriched to exceed its natural abundance of 0.015% should be considered unnatural and, as a result, more novel than their non-enriched counterparts.
本発明の化合物は、塩又は溶媒和物の形態で存在していてもよく、場合により塩又は溶媒和物の形態で投与されてもよいことを認識するべきである。本発明は、上記の化合物及びそれらの修飾物のいずれか1つの任意の薬学的に許容可能な塩及び溶媒和物を包含する。例えば、当技術分野において良く知られている手順にしたがって、本発明の化合物を、様々な有機及び無機の酸及び塩基に由来するそれらの薬学的に許容可能な塩へ転化し、そのような形態で使用することは、本発明の範囲内である。 It should be recognized that the compounds of the present invention may exist and may optionally be administered in the form of salts or solvates. The present invention encompasses any pharma- ceutically acceptable salts and solvates of any one of the above compounds and modifications thereof. For example, it is within the scope of the present invention to convert the compounds of the present invention into their pharma- ceutically acceptable salts derived from various organic and inorganic acids and bases, and to use them in such forms, according to procedures well known in the art.
本発明の化合物が遊離塩基の形態を有する場合、遊離塩基の形態の化合物を、薬学的に許容可能な無機又は有機酸と反応させることにより、薬学的に許容可能な酸付加塩、例えば、ハロゲン化水素酸塩、例えば塩酸塩、臭化水素酸塩、ヨウ化水素酸塩など;他の鉱酸、例えば硫酸塩、硝酸塩、リン酸塩など;並びにアルキル及びモノアリールスルホン酸塩、例えばエタンスルホン酸塩、トルエンスルホン酸塩、及びベンゼンスルホン酸塩など;並びに他の有機酸及びそれらの対応する塩、例えば酢酸塩、酒石酸塩、マレイン酸塩、コハク酸塩、クエン酸塩、安息香酸塩、サリチル酸塩、及びアスコルビン酸塩などとして化合物を調製できる。本発明のさらなる酸付加塩としては、限定はされないが、アジピン酸塩、アルギン酸塩、アルギニン酸塩、アスパラギン酸塩、重硫酸塩、重亜硫酸塩、臭化物、酪酸塩、カンホレート、カンフルスルホン酸塩、カプリル酸塩、塩化物、クロロ安息香酸塩、シクロペンタンプロピオン酸塩、ジグルコン酸塩、二水素リン酸塩、ジニトロ安息香酸塩、ドデシル硫酸塩、フマル酸塩、ガラクタル酸塩(ムチン酸由来)、ガラクツロン酸塩、グルコヘプトン酸塩、グルコン酸塩、グルタミン酸塩、グリセロリン酸塩、ヘミコハク酸塩、ヘミ硫酸塩、ヘプタン酸塩、ヘキサン酸塩、馬尿酸塩、2-ヒドロキシエタンスルホネート、ヨウ化物、イセチオネート、イソ酪酸塩、乳酸塩、ラクトビオン酸塩、マロン酸塩、マンデル酸塩、メタリン酸塩、メタンスルホン酸塩、メチル安息香酸塩、一水素リン酸塩、2-ナフタレンスルホン酸塩、ニコチン酸塩、シュウ酸塩、オレイン酸塩、パモ酸塩、ペクチニン酸塩(pectinate)、過硫酸塩、フェニル酢酸塩、3-フェニルプロピオン酸塩、ホスホン酸塩、及びフタル酸塩が挙げられる。遊離塩基の形態は、典型的には極性溶媒中の溶解性などの物理特性においてそれらのそれぞれの塩の形態とはやや異なるが、それ以外の点で本発明の目的に関して塩はそれらのそれぞれの遊離塩基の形態と同等であることを認識するべきである。 When the compounds of the present invention have a free base form, the compounds can be prepared as pharma- ceutically acceptable acid addition salts, such as hydrohalides, e.g., hydrochlorides, hydrobromides, hydroiodides, and the like; other mineral acids, e.g., sulfates, nitrates, phosphates, and the like; and alkyl and monoaryl sulfonates, e.g., ethanesulfonates, toluenesulfonates, and benzenesulfonates, and the like; and other organic acids and their corresponding salts, e.g., acetates, tartrates, maleates, succinates, citrates, benzoates, salicylates, and ascorbates, and the like, by reacting the compounds in their free base form with a pharma- ceutically acceptable inorganic or organic acid. Further acid addition salts of the present invention include, but are not limited to, adipate, alginate, alginate, aspartate, bisulfate, bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate, chloride, chlorobenzoate, cyclopentanepropionate, digluconate, dihydrogen phosphate, dinitrobenzoate, dodecyl sulfate, fumarate, galactarate (from mucic acid), galacturonate, glucoheptonate, gluconate, glutamate, glycerophosphate, hemiphosphate, glycero ... These include succinate, hemisulfate, heptanoate, hexanoate, hippurate, 2-hydroxyethanesulfonate, iodide, isethionate, isobutyrate, lactate, lactobionate, malonate, mandelate, metaphosphate, methanesulfonate, methylbenzoate, monohydrogen phosphate, 2-naphthalenesulfonate, nicotinate, oxalate, oleate, pamoate, pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphonate, and phthalate. It should be recognized that the free base forms typically differ somewhat in physical properties, such as solubility in polar solvents, from their respective salt forms, but that the salts are otherwise equivalent to their respective free base forms for purposes of the present invention.
本発明の化合物が遊離酸の形態を有する場合、遊離酸の形態の化合物を薬学的に許容可能な無機又は有機塩基と反応させることにより、薬学的に許容可能な塩基付加塩を調製することができる。そのような塩基の例は、水酸化カリウム、ナトリウム、及びリチウムを含めたアルカリ金属水酸化物;アルカリ土類金属水酸化物、例えば水酸化バリウム及びカルシウムなど;アルカリ金属アルコキシド、例えば、カリウムエタノレート及びナトリウムプロパノレート;並びに様々な有機塩基、例えば水酸化アンモニウム、ピペリジン、ジエタノールアミン、及びN-メチルグルタミンなどである。本発明の化合物のアルミニウム塩も含まれる。本発明のさらなる塩基塩としては、限定はされないが、銅、第2鉄、第1鉄、リチウム、マグネシウム、第2マンガン、第1マンガン、カリウム、ナトリウム、及び亜鉛の塩が挙げられる。有機塩基塩としては、限定はされないが、第1級、第2級、及び第3級アミン、天然置換アミンを含めた置換アミン、環状アミン、及び塩基性イオン交換樹脂、例えば、アルギニン、ベタイン、カフェイン、クロロプロカイン、コリン、N,N'-ジベンジルエチレンジアミン(ベンザチン)、ジシクロヘキシルアミン、ジエタノールアミン、2-ジエチルアミノエタノール、2-ジメチルアミノエタノール、エタノールアミン、エチレンジアミン、N-エチルモルホリン、N-エチルピペリジン、グルカミン、グルコサミン、ヒスチジン、ヒドラバミン、イソプロピルアミン、リドカイン、リジン、メグルミン、N-メチル-D-グルカミン、モルホリン、ピペラジン、ピペリジン、ポリアミン樹脂、プロカイン、プリン、テオブロミン、トリエタノールアミン、トリエチルアミン、トリメチルアミン、トリプロピルアミン、及びトリス-(ヒドロキシメチル)-メチルアミン(トロメタミン)の塩が挙げられる。遊離酸の形態は、典型的には極性溶媒中の溶解性などの物理特性においてそれらのそれぞれの塩の形態とはやや異なるが、それ以外の点で本発明の目的に関して塩はそれらのそれぞれの遊離酸の形態と同等であることを認識するべきである。 When the compounds of the present invention have a free acid form, pharma- ceutically acceptable base addition salts can be prepared by reacting the free acid form of the compound with a pharma- ceutically acceptable inorganic or organic base. Examples of such bases are alkali metal hydroxides, including potassium, sodium, and lithium hydroxide; alkaline earth metal hydroxides, such as barium and calcium hydroxide; alkali metal alkoxides, such as potassium ethanolate and sodium propanolate; and various organic bases, such as ammonium hydroxide, piperidine, diethanolamine, and N-methylglutamine. Aluminum salts of the compounds of the present invention are also included. Additional base salts of the present invention include, but are not limited to, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, and zinc salts. Organic base salts include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, chloroprocaine, choline, N,N'-dibenzylethylenediamine (benzathine), dicyclohexylamine, diethanolamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lidocaine, lysine, meglumine, N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethanolamine, triethylamine, trimethylamine, tripropylamine, and tris-(hydroxymethyl)-methylamine (tromethamine). It should be recognized that the free acid forms typically differ somewhat in physical properties, such as solubility in polar solvents, from their respective salt forms, but that the salts are otherwise equivalent to their respective free acid forms for purposes of the present invention.
一態様において、薬学的に許容可能な塩は、塩酸塩、臭化水素酸塩、メタンスルホン酸塩、トルエンスルホン酸塩、酢酸塩、フマル酸塩、硫酸塩、重硫酸塩、コハク酸塩、クエン酸塩、リン酸塩、マレイン酸塩、硝酸塩、酒石酸塩、安息香酸塩、重炭酸塩、炭酸塩、水酸化ナトリウム塩、水酸化カルシウム塩、水酸化カリウム塩、トロメタミン塩、又はそれらの混合物である。 In one embodiment, the pharma- ceutically acceptable salt is a hydrochloride, hydrobromide, methanesulfonate, toluenesulfonate, acetate, fumarate, sulfate, bisulfate, succinate, citrate, phosphate, maleate, nitrate, tartrate, benzoate, bicarbonate, carbonate, sodium hydroxide, calcium hydroxide, potassium hydroxide, tromethamine salt, or mixtures thereof.
第3級窒素含有基を含む本発明の化合物は、(C1-4)アルキルハロゲン化物、例えば、メチル、エチル、イソプロピル、及びtert-ブチルの塩化物、臭化物、及びヨウ化物;ジ-(C1-4)アルキルスルフェート、例えば、ジメチル、ジエチル、及びジアミルスルフェート;アルキルハロゲン化物、例えば、デシル、ドデシル、ラウリル、ミリスチル、及びステアリルの塩化物、臭化物、及びヨウ化物;並びにアリール(C1-4)アルキルハロゲン化物、例えばベンジルクロリド及びフェネチルブロミドなどの薬剤で四級化させてもよい。そのような塩は水溶性でもあり油溶性でもある本発明の化合物の調製を可能にする。 Compounds of the invention containing tertiary nitrogen-containing groups may be quaternized with agents such as (C 1-4 ) alkyl halides, e.g., methyl, ethyl, isopropyl, and tert-butyl chlorides, bromides, and iodides; di-(C 1-4 ) alkyl sulfates, e.g., dimethyl, diethyl, and diamyl sulfate; alkyl halides, e.g., decyl, dodecyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; and aryl(C 1-4 ) alkyl halides, e.g., benzyl chloride and phenethyl bromide. Such salts allow for the preparation of compounds of the invention that are both water- and oil-soluble.
アミン-N-オキシド及びN-オキシドとしても知られる、第3級窒素原子を有する抗癌剤であるアミンオキシドは、プロドラッグとして開発されてきた[Mol Cancer Therapy. 2004年3月; 3(3):233~44頁]。第3級窒素原子を含む本発明の化合物は、過酸化水素(H2O2)、カロ酸、又はメタクロロペルオキシ安息香酸(mCPBA)のような過酸などの薬剤によって酸化させてアミンオキシドを得ることができる。 Amine oxides, also known as amine-N-oxides and N-oxides, which are anticancer drugs with a tertiary nitrogen atom, have been developed as prodrugs [Mol Cancer Therapy. March 2004; 3(3):233-44]. Compounds of the invention containing a tertiary nitrogen atom can be oxidized to give amine oxides by agents such as hydrogen peroxide ( H2O2 ), Caro's acid, or peracids such as metachloroperoxybenzoic acid (mCPBA).
本明細書で開示された化合物はbcl-2阻害剤である。本発明の医薬組成物は、1種以上のbcl-2阻害剤、又はその薬学的に許容可能な塩、及び薬学的に許容可能な担体又は希釈剤を含む。 The compounds disclosed herein are bcl-2 inhibitors. The pharmaceutical compositions of the present invention comprise one or more bcl-2 inhibitors, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier or diluent.
「薬学的に許容可能な担体」及び「薬学的に許容可能な希釈剤」は、活性剤の製剤化並びに/又は対象への活性剤の投与及び/若しくは対象による吸収を補助し、対象に著しい有害な毒物学的効果を引き起こさずに、本開示の組成物に含めることができる物質を指す。薬学的に許容可能な担体及び/又は希釈剤の非限定的例として、水、NaCl、生理食塩水、乳酸リンゲル液、通常のスクロース、通常のグルコース、バインダー、充填剤、崩壊剤、潤滑剤、コーティング剤、甘味料、香料、塩溶液(例えば、リンゲル溶液)、アルコール、油、ゼラチン、炭水化物、例えば、ラクトース、アミロース又はデンプン、脂肪酸エステル、ヒドロキシメチルセルロース、ポリビニルピロリジン、及び着色剤などが挙げられる。そのような調製物は、滅菌することができ、所望する場合、本明細書に提供されている化合物と有害に反応したり、本明細書に提供されている化合物の活性を妨げたりすることがない助剤、例えば、潤滑剤、保存料、安定化剤、湿潤剤、乳化剤、浸透圧に影響を与える塩、緩衝剤、着色剤、及び/又は芳香族物質などと混合することができる。当業者であれば、他の医薬賦形剤が開示化合物との使用に適していることを認識している。 "Pharmaceutically acceptable carrier" and "Pharmaceutically acceptable diluent" refer to substances that aid in the formulation and/or administration of an active agent to and/or absorption by a subject and can be included in the compositions of the present disclosure without causing significant adverse toxicological effects to the subject. Non-limiting examples of pharmaceutically acceptable carriers and/or diluents include water, NaCl, saline, lactated Ringer's solution, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings, salt solutions (e.g., Ringer's solution), alcohol, oils, gelatin, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine, and colorants. Such preparations can be sterilized and, if desired, mixed with auxiliary substances that do not adversely react with or interfere with the activity of the compounds provided herein, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring agents, and/or aromatic substances. Those skilled in the art will recognize that other pharmaceutical excipients are suitable for use with the disclosed compounds.
本発明の医薬組成物は、そのための1つ以上の薬学的に許容可能な担体及び/又は希釈剤、例えば、ラクトース、デンプン、セルロース及びブドウ糖を場合により含む。他の賦形剤、例えば、香味剤、甘味料、及び保存料、例えば、メチル、エチル、プロピル及びブチルパラベンを含むこともできる。適切な賦形剤のより完全な一覧表は、Handbook of Pharmaceutical Excipients(第5版、Pharmaceutical Press(2005年))において見ることができる。当業者であれば、様々な種類の投与経路に適した製剤の調製の方法を承知している。適切な製剤の選択及び調製のための従来の手順及び成分は、例えば、Remington's Pharmaceutical Sciences(2003年、第20版)及びThe United States Pharmacopeia: The National Formulary (USP 24NF19)1999年出版に記載されている。担体、希釈剤及び/又は賦形剤は、医薬組成物の他の成分と適合性があり、そのレシピエントに有害ではないという意味で「許容可能」である。 The pharmaceutical compositions of the present invention optionally include one or more pharma- ceutically acceptable carriers and/or diluents therefor, such as lactose, starch, cellulose, and glucose. Other excipients, such as flavorings, sweeteners, and preservatives, such as methyl, ethyl, propyl, and butyl parabens, may also be included. A more complete listing of suitable excipients can be found in the Handbook of Pharmaceutical Excipients, 5th ed., Pharmaceutical Press (2005). The skilled artisan will know how to prepare formulations suitable for various types of administration routes. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington's Pharmaceutical Sciences, 20th ed., 2003, and The United States Pharmacopeia: The National Formulary (USP 24NF19), 1999 publication. A carrier, diluent, and/or excipient is "acceptable" in the sense of being compatible with the other ingredients of the pharmaceutical composition and not deleterious to the recipient thereof.
本発明の医薬組成物は他の従来の薬学的に不活性な薬剤をさらに含むことができる。担体又は希釈剤として一般に使用されている任意の不活性賦形剤、例えば糖、ポリアルコール、可溶性ポリマー、塩、及び脂質などを、本発明の組成物において使用してもよい。採用することができる糖及びポリアルコールとしては、限定はされないが、ラクトース、スクロース、マンニトール、及びソルビトールが挙げられる。採用することができる可溶性ポリマーの例となるものは、ポリオキシエチレン、ポロキサマー、ポリビニルピロリドン、及びデキストランである。有用な塩としては、限定はされないが、塩化ナトリウム、塩化マグネシウム、及び塩化カルシウムが挙げられる。採用することができる脂質としては、限定はされないが、脂肪酸、グリセリン脂肪酸エステル、糖脂質、及びリン脂質が挙げられる。 The pharmaceutical compositions of the present invention may further include other conventional pharma- ceutical inactive agents. Any inert excipients commonly used as carriers or diluents, such as sugars, polyalcohols, soluble polymers, salts, and lipids, may be used in the compositions of the present invention. Sugars and polyalcohols that may be employed include, but are not limited to, lactose, sucrose, mannitol, and sorbitol. Exemplary soluble polymers that may be employed are polyoxyethylene, poloxamer, polyvinylpyrrolidone, and dextran. Useful salts include, but are not limited to, sodium chloride, magnesium chloride, and calcium chloride. Lipids that may be employed include, but are not limited to, fatty acids, glycerol fatty acid esters, glycolipids, and phospholipids.
さらに、本発明の医薬組成物は、バインダー(例えば、アカシア、コーンスターチ、ゼラチン、カルボマー、エチルセルロース、グアーガム、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポビドン)、崩壊剤(例えば、コーンスターチ、ジャガイモデンプン、アルギン酸、二酸化ケイ素、クロスカルメロースナトリウム、クロスポビドン、グアーガム、ナトリウムデンプングリコレート、Primogel)、様々なpH及びイオン強度の緩衝剤(例えば、トリスHCL、酢酸塩、リン酸塩)、添加剤、例えば表面への吸収を防ぐためのアルブミン又はゼラチンなど、洗剤(例えば、Tween 20、Tween 80、Pluronic F68、胆汁酸塩)、プロテアーゼ阻害剤、界面活性剤(例えば、ラウリル硫酸ナトリウム)、浸透促進剤、可溶化剤(例えば、グリセリン、ポリエチレングリセリン、シクロデキストリン)、流動促進剤(例えば、コロイド状二酸化ケイ素)、抗酸化剤(例えば、アスコルビン酸、メタ重亜硫酸ナトリウム、ブチル化ヒドロキシアニソール)、安定化剤(例えば、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース)、増粘剤(例えば、カルボマー、コロイド状二酸化ケイ素、エチルセルロース、グアーガム)、甘味料(例えば、スクロース、アスパルテーム、クエン酸)、香味剤(例えば、ペパーミント、サルチル酸メチル、又はオレンジ香味料)、保存料(例えば、チメロサール、ベンジルアルコール、パラベン)、潤滑剤(例えば、ステアリン酸、ステアリン酸マグネシウム、ポリエチレングリコール、ラウリル硫酸ナトリウム)、流動助剤(例えば、コロイド状二酸化ケイ素)、可塑剤(例えば、フタル酸ジエチル、クエン酸トリエチル)、乳化剤(例えば、カルボマー、ヒドロキシプロピルセルロース、ラウリル硫酸ナトリウム、メチルセルロース、ヒドロキシエチルセルロース、カルボキシメチルセルロースナトリウム)、ポリマーコーティング(例えば、ポロキサマー又はポロキサミン)、コーティング剤及び膜形成剤(例えば、エチルセルロース、アクリレート、ポリメタクリレート)及び/又は補助剤をさらに含んでいてもよい。 In addition, the pharmaceutical compositions of the present invention may contain binders (e.g., acacia, corn starch, gelatin, carbomer, ethylcellulose, guar gum, hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone), disintegrants (e.g., corn starch, potato starch, alginic acid, silicon dioxide, croscarmellose sodium, crospovidone, guar gum, sodium starch glycolate, Primogel), buffers of various pH and ionic strengths (e.g., Tris HCL, acetate, phosphate), additives such as albumin or gelatin to prevent absorption onto surfaces, detergents (e.g., Tween 20, Tween 80, Pluronic F68, bile salts), protease inhibitors, surfactants (e.g., sodium lauryl sulfate), penetration enhancers, solubilizers (e.g., glycerin, polyethylene glycerin, cyclodextrin), glidants (e.g., colloidal silicon dioxide), antioxidants (e.g., ascorbic acid, sodium metabisulfite, butylated hydroxyanisole), stabilizers (e.g., hydroxypropylcellulose, hydroxypropylmethylcellulose), thickeners (e.g., carbomer, colloidal silicon dioxide, ethylcellulose, guar gum), sweeteners (e.g., sucrose, aspartame, citric acid), flavoring agents (e.g., peppermint, methyl salicylate, or orange flavor), preservatives (e.g., For example, thimerosal, benzyl alcohol, parabens), lubricants (e.g., stearic acid, magnesium stearate, polyethylene glycol, sodium lauryl sulfate), flow aids (e.g., colloidal silicon dioxide), plasticizers (e.g., diethyl phthalate, triethyl citrate), emulsifiers (e.g., carbomer, hydroxypropyl cellulose, sodium lauryl sulfate, methylcellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose), polymer coatings (e.g., poloxamers or poloxamines), coating and film formers (e.g., ethyl cellulose, acrylates, polymethacrylates) and/or auxiliary agents.
一実施形態において、インプラント及びマイクロカプセル化送達システムを含めた放出制御製剤などの、医薬組成物は、体内からの急速な排出から化合物を守る担体と共に調製される。エチレン酢酸ビニル、ポリ無水物、ポリグリコール酸、コラーゲン、ポリオルトエステル、及びポリ乳酸などの、生分解性の生体適合性ポリマーを使用できる。そのような製剤の調製方法は当業者にとって明らかである。材料はAlza Corporation社及びNova Pharmaceuticals, Inc.社から購入することもできる。リポソーム懸濁液(ウイルス抗原に対するモノクローナル抗体を有する感染細胞へ標的化されたリポソームを含む)も薬学的に許容可能な担体として使用できる。これらは当業者に公知の方法、例えば米国特許第4,522,811号に記載の方法にしたがって調製できる。 In one embodiment, pharmaceutical compositions, such as controlled release formulations, including implants and microencapsulated delivery systems, are prepared with carriers that will protect the compound against rapid elimination from the body. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparing such formulations will be apparent to those of skill in the art. Materials can also be purchased from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies against viral antigens) can also be used as pharma- ceutically acceptable carriers. These can be prepared according to methods known to those of skill in the art, for example, those described in U.S. Pat. No. 4,522,811.
さらに、本発明は、任意の固体又は液体の物理的形態の本発明の化合物を含む医薬組成物を包含する。例えば、化合物は結晶形態、アモルファス形態であってもよく、任意の粒径を有していてもよい。粒子は、微粒子化されていてもよく、又は凝集していてもよく、粒状顆粒、粉末、オイル、油性懸濁液、又は固体若しくは液体の物理的形態の任意の他の形態であってもよい。 Additionally, the present invention encompasses pharmaceutical compositions comprising the compounds of the present invention in any solid or liquid physical form. For example, the compounds may be in crystalline or amorphous form and may have any particle size. The particles may be micronized or agglomerated, and may be in the form of granules, powders, oils, oily suspensions, or any other form of solid or liquid physical form.
本発明による化合物が不十分な溶解性を示す場合、化合物を可溶化させる方法を使用してもよい。そのような方法は当業者に公知であり、限定はされないが、pH調整及び塩形成、共溶媒の使用、例えばエタノール、プロピレングリコール、ポリエチレングリコール(PEG) 300、PEG 400、DMA (10~30%)、DMSO (10~20%)、NMP (10~20%)など、界面活性剤の使用、例えばポリソルベート(polysorbate) 80、ポリソルベート20 (1~10%)、クレモフォール(Cremophor) EL、クレモフォールRH40、クレモフォールRH60 (5~10%)、プルロニック(Pluronic) F68/ポロキサマー(Poloxamer) 188 (20~50%)、ソルトール(Solutol) HS15 (20~50%)、ビタミンE TPGS、及びd-α-トコフェリルPEG 1000スクシネート(20~50%)など、複合体形成の使用、例えばHPβCD及びSBEβCD (10~40%)など、並びに先進的な方法の使用、例えばミセル、ポリマーの添加、ナノ粒子懸濁液、及びリポソーム形成などが挙げられる。 If the compounds according to the present invention exhibit insufficient solubility, methods for solubilizing the compounds may be used. Such methods are known to those skilled in the art and include, but are not limited to, pH adjustment and salt formation, the use of co-solvents such as ethanol, propylene glycol, polyethylene glycol (PEG) 300, PEG 400, DMA (10-30%), DMSO (10-20%), NMP (10-20%), the use of surfactants such as polysorbate 80, polysorbate 20 (1-10%), Cremophor EL, Cremophor RH40, Cremophor RH60 (5-10%), Pluronic F68/Poloxamer 188 (20-50%), Solutol HS15 (20-50%), Vitamin E TPGS, and d-α-tocopheryl PEG 1000 succinate (20-50%), the use of complexation such as HPβCD and SBEβCD. (10-40%), as well as the use of advanced methods such as micelles, the addition of polymers, nanoparticle suspensions, and liposome formation.
多様な投与方法を本発明の化合物と併せて使用してもよい。本発明の化合物は、経口、非経口、腹腔内、静脈内、動脈内、経皮、舌下、筋肉内、直腸内、バッカル経由(transbuccally)、鼻腔内、リポソーム製剤、吸入、経膣、眼内、局所送達(例えばカテーテル又はステントにより)、皮下、脂肪内(intraadiposally)、関節内、又はくも膜下腔内で、投与又は同時投与してもよい。本発明による化合物はまた、徐放剤形で投与又は同時投与してもよい。化合物は、使用しようとする投与の経路に適した方法で調合された、ガス、液体、半液体、又は固体の形態であってもよい。経口投与に関して、適切な固体経口製剤としては、錠剤、カプセル、ピル、顆粒、ペレット、サシェ、及び発泡性粉末などが挙げられる。適切な液体経口製剤としては、溶液、懸濁液、分散液、エマルション、オイルなどが挙げられる。非経口投与に関しては、凍結乾燥粉末の再構成が典型的に使用される。 A variety of administration methods may be used in conjunction with the compounds of the present invention. The compounds of the present invention may be administered or co-administered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, in liposomal formulations, by inhalation, vaginally, intraocularly, topically delivered (e.g., by catheter or stent), subcutaneously, intraadiposally, intraarticularly, or intrathecally. The compounds according to the present invention may also be administered or co-administered in sustained release dosage forms. The compounds may be in gas, liquid, semi-liquid, or solid form, formulated in a manner appropriate for the route of administration to be used. For oral administration, suitable solid oral formulations include tablets, capsules, pills, granules, pellets, sachets, and effervescent powders. Suitable liquid oral formulations include solutions, suspensions, dispersions, emulsions, oils, and the like. For parenteral administration, reconstitution of lyophilized powders is typically used.
本明細書で使用する場合、「アシル」は、式-C(O)-Rにより表されるカルボニル含有置換基を意味し、式中Rは、H、アルキル、炭素環、複素環、炭素環で置換されたアルキル、又は複素環で置換されたアルキルであり、ここでアルキル、アルコキシ、炭素環、及び複素環は、本明細書において定義される通りである。アシル基としては、アルカノイル(例えばアセチル)、アロイル(例えばベンゾイル)、及びヘテロアロイルが挙げられる。 As used herein, "acyl" means a carbonyl-containing substituent represented by the formula -C(O)-R, where R is H, alkyl, carbocycle, heterocycle, carbocycle-substituted alkyl, or heterocycle-substituted alkyl, where alkyl, alkoxy, carbocycle, and heterocycle are as defined herein. Acyl groups include alkanoyl (e.g., acetyl), aroyl (e.g., benzoyl), and heteroaroyl.
「脂肪族」は、構成炭素原子の直鎖又は分岐鎖の配置によって特徴づけられる部分を意味し、飽和であるか又は1つ以上の二重結合若しくは三重結合により部分不飽和であってもよい。 "Aliphatic" means a moiety characterized by a straight or branched arrangement of the constituent carbon atoms, which may be saturated or partially unsaturated with one or more double or triple bonds.
「アルキル」という用語は、1~20個の炭素原子(例えば、C1~C10、C1~C6)を含有する直鎖又は分岐鎖の炭化水素を指す。アルキルの例としては、限定はされないが、メチル、メチレン、エチル、エチレン、n-プロピル、i-プロピル、n-ブチル、i-ブチル、及びt-ブチルが挙げられる。好ましくは、アルキル基は1~10個の炭素原子を有する。より好ましくは、アルキル基は1~4個の炭素原子を有する。 The term "alkyl" refers to a straight or branched chain hydrocarbon containing 1 to 20 carbon atoms (e.g., C 1 -C 10 , C 1 -C 6 ). Examples of alkyl include, but are not limited to, methyl, methylene, ethyl, ethylene, n-propyl, i-propyl, n-butyl, i-butyl, and t-butyl. Preferably, an alkyl group has 1 to 10 carbon atoms. More preferably, an alkyl group has 1 to 4 carbon atoms.
「アルケニル」という用語は、2~20個の炭素原子(例えば、C2~C10、C2~C6)及び1つ以上の二重結合を含有する直鎖又は分岐鎖の炭化水素を指す。アルケニルの例としては、限定はされないが、エテニル、プロぺニル、及びアリルが挙げられる。好ましくは、アルキレン基は2~10個の炭素原子を有する。より好ましくは、アルキレン基は2~4個の炭素原子を有する。 The term "alkenyl" refers to a straight or branched chain hydrocarbon containing 2 to 20 carbon atoms (e.g., C2 - C10 , C2 - C6 ) and one or more double bonds. Examples of alkenyl include, but are not limited to, ethenyl, propenyl, and allyl. Preferably, an alkylene group has 2 to 10 carbon atoms. More preferably, an alkylene group has 2 to 4 carbon atoms.
「アルキニル」という用語は、2~20個の炭素原子(例えば、C2~C10、C2~C6)及び1つ以上の三重結合を含有する直鎖又は分岐鎖の炭化水素を指す。アルキニルの例としては、限定はされないが、エチニル、1-プロピニル、1-及び2-ブチニル、並びに1-メチル-2-ブチニルが挙げられる。好ましくは、アルキニル基は2~10個の炭素原子を有する。より好ましくは、アルキニル基は2~4個の炭素原子を有する。 The term "alkynyl" refers to a straight or branched chain hydrocarbon containing 2 to 20 carbon atoms (e.g., C2 - C10 , C2 - C6 ) and one or more triple bonds. Examples of alkynyl include, but are not limited to, ethynyl, 1-propynyl, 1- and 2-butynyl, and 1-methyl-2-butynyl. Preferably, an alkynyl group has 2 to 10 carbon atoms. More preferably, an alkynyl group has 2 to 4 carbon atoms.
「アルキルアミノ」という用語は、-N(R)-アルキルを指し、ここでRは、H、アルキル、アルケニル、アルキニル、シクロアルキル、シクロアルケニル、ヘテロシクロアルキル、ヘテロシクロアルケニル、アリール、又はヘテロアリールであってもよい。 The term "alkylamino" refers to -N(R)-alkyl, where R may be H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl.
「アルコキシ」は、さらなるアルキル置換基を有する酸素部分を意味する。 "Alkoxy" means an oxygen moiety having a further alkyl substituent.
「アルコキシカルボニル」は、カルボニル基に結合したアルコキシ基を意味する。 "Alkoxycarbonyl" means an alkoxy group bonded to a carbonyl group.
「オキソアルキル」は、カルボニル基でさらに置換されたアルキルを意味する。カルボニル基は、アルデヒド、ケトン、エステル、アミド、酸、又は酸塩化物であってもよい。 "Oxoalkyl" means an alkyl further substituted with a carbonyl group. The carbonyl group may be an aldehyde, ketone, ester, amide, acid, or acid chloride.
「シクロアルキル」という用語は、3~30個の炭素原子(例えば、C3~C12、C3~C8、C3~C6)を有する飽和炭化水素環系を指す。シクロアルキルの例としては、限定はされないが、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル、及びシクロオクチルが挙げられる。「シクロアルケニル」という用語は、3~30個の炭素(例えば、C3~C12)及び1つ以上の二重結合を有する非芳香族炭化水素環系を指す。例としては、シクロペンテニル、シクロヘキセニル、及びシクロヘプテニルが挙げられる。 The term "cycloalkyl" refers to a saturated hydrocarbon ring system having 3 to 30 carbon atoms (e.g., C3 - C12 , C3 - C8 , C3 - C6 ). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The term "cycloalkenyl" refers to a non-aromatic hydrocarbon ring system having 3 to 30 carbons (e.g., C3 - C12 ) and one or more double bonds. Examples include cyclopentenyl, cyclohexenyl, and cycloheptenyl.
「ヘテロシクロアルキル」という用語は、同じでも異なっていてもよい、1~4個のヘテロ原子(例えば、O、N、S、B、P、Si、又はSe)を有する、飽和又は不飽和の非芳香族の5~8員単環系、8~12員二環系、又は11~14員三環系を指す。ヘテロシクロアルキル基の例としては、限定はされないが、ピペラジニル、ピロリジニル、ジオキサニル、モルホリニル、及びテトラヒドロフラニルが挙げられる。 The term "heterocycloalkyl" refers to a saturated or unsaturated non-aromatic 5- to 8-membered monocyclic ring system, 8- to 12-membered bicyclic ring system, or 11- to 14-membered tricyclic ring system having 1 to 4 heteroatoms (e.g., O, N, S, B, P, Si, or Se), which may be the same or different. Examples of heterocycloalkyl groups include, but are not limited to, piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, and tetrahydrofuranyl.
「ヘテロシクロアルケニル」という用語は、1つ以上のヘテロ原子(O、N、S、P、B、Si、又はSeなど)及び1つ以上の二重結合を有する、非芳香族の5~8員単環系、8~12員二環系、又は11~14員三環系を指す。 The term "heterocycloalkenyl" refers to a non-aromatic 5- to 8-membered monocyclic ring system, 8- to 12-membered bicyclic ring system, or 11- to 14-membered tricyclic ring system having one or more heteroatoms (such as O, N, S, P, B, Si, or Se) and one or more double bonds.
「アリール」という用語は、6-炭素単環式、10-炭素二環式、14-炭素三環式の芳香族環系を指す。アリール基の例としては、限定はされないが、フェニル、ナフチル、及びアントラセニルが挙げられる。 The term "aryl" refers to a 6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon tricyclic aromatic ring system. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl.
「ヘテロアリール」という用語は、1つ以上のヘテロ原子(O、N、S、P、又はSeなど)を有する、芳香族の5~8員単環系、8~12員二環系、又は11~14員三環系を指す。ヘテロアリール基の例としては、ピリジル、フリル、イミダゾリル、ベンゾイミダゾリル、ピリミジニル、チエニル、キノリニル、インドリル、及びチアゾリルが挙げられる。 The term "heteroaryl" refers to an aromatic 5- to 8-membered monocyclic, 8- to 12-membered bicyclic, or 11- to 14-membered tricyclic ring system having one or more heteroatoms (such as O, N, S, P, or Se). Examples of heteroaryl groups include pyridyl, furyl, imidazolyl, benzimidazolyl, pyrimidinyl, thienyl, quinolinyl, indolyl, and thiazolyl.
上記のアルキル、アルケニル、アルキニル、シクロアルキル、ヘテロシクロアルキル、シクロアルケニル、ヘテロシクロアルケニル、アルキルアミノ、アリール、及びヘテロアリールは、置換及び非置換部分の両方を含む。アルキルアミノ、シクロアルキル、ヘテロシクロアルキル、シクロアルケニル、ヘテロシクロアルケニル、アリール、及びヘテロアリール上の考えられる置換基としては、限定はされないが、C1~C10アルキル、C2~C10アルケニル、C2~C10アルキニル、C3~C20シクロアルキル、C3~C20シクロアルケニル、C1~C20ヘテロシクロアルキル、C1~C20ヘテロシクロアルケニル、C1~C10アルコキシ、アリール、アリールオキシ、ヘテロアリール、ヘテロアリールオキシ、アミノ、C1~C10アルキルアミノ、アリールアミノ、ヒドロキシ、ハロ、オキソ(O=)、チオキソ(S=)、チオ、シリル、C1~C10アルキルチオ、アリールチオ、C1~C10アルキルスルホニル、アリールスルホニル、アシルアミノ、アミノアシル、アミノチオアシル、アミジノ、メルカプト、アミド、チオウレイド、チオシアナト、スルホンアミド、グアニジン、ウレイド、シアノ、ニトロ、アシル、チオアシル、アシルオキシ、カルバミド、カルバミル、カルボキシル、及びカルボン酸エステルが挙げられる。他方で、アルキル、アルケニル、又はアルキニル上の考えられる置換基としては、C1~C10アルキルを除いて上記で列挙される置換基のすべてが挙げられる。シクロアルキル、シクロアルケニル、ヘテロシクロアルキル、ヘテロシクロアルケニル、アリール、及びヘテロアリールは互いに縮合していてもよい。 The above alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, alkylamino, aryl, and heteroaryl include both substituted and unsubstituted moieties. Possible substituents on alkylamino, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl include, but are not limited to, C1 - C10 alkyl, C2-C10 alkenyl, C2 - C10 alkynyl, C3 - C20 cycloalkyl , C3 - C20 cycloalkenyl, C1 - C20 heterocycloalkyl, C1-C20 heterocycloalkenyl , C1 - C10 alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, amino, C1 - C10 alkylamino, arylamino, hydroxy , halo, oxo (O=), thioxo (S=), thio, silyl, C1 - C10 alkylthio, arylthio ... 10 alkylsulfonyl, arylsulfonyl, acylamino, aminoacyl, aminothioacyl, amidino, mercapto, amido, thioureido, thiocyanato, sulfonamido, guanidine, ureido, cyano, nitro, acyl, thioacyl, acyloxy, carbamido, carbamyl, carboxyl, and carboxylic acid ester. On the other hand, possible substituents on alkyl, alkenyl, or alkynyl include all of the substituents listed above except for C 1 -C 10 alkyl. Cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl may be fused to each other.
「アミノ」は、2つのさらなる置換基を有する窒素部分を意味し、ここで各置換基は水素、又は窒素へアルファ結合した炭素原子を有する。別段の指示がない限り、アミノ部分を含有する本発明の化合物は、その保護誘導体を含んでいてもよい。アミノ部分の適切な保護基としては、アセチル、tert-ブトキシカルボニル、ベンジルオキシカルボニルなどが挙げられる。 "Amino" means a nitrogen moiety having two further substituents, where each substituent has a hydrogen or a carbon atom alpha-bonded to the nitrogen. Unless otherwise indicated, compounds of the invention containing an amino moiety may include protected derivatives thereof. Suitable protecting groups for amino moieties include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like.
「芳香族」は、構成原子が不飽和環系を作っている部分を意味し、環系のすべての原子はsp2混成であり、π電子の総数は4n+2に等しい。芳香族環は、環原子が炭素原子のみであってもよく又は炭素及び非炭素原子を含んでいてもよい(ヘテロアリールを参照)。 "Aromatic" means a moiety whose constituent atoms make up an unsaturated ring system, all atoms in the ring system are sp2 hybridized, and the total number of pi electrons is equal to 4n+2. An aromatic ring may contain only carbon atoms or may contain carbon and non-carbon atoms (see Heteroaryl).
「カルバモイル」は、-OC(O)NRaRb基を意味し、式中、Ra及びRbはそれぞれ独立に、水素又は炭素原子が窒素に対してアルファ位である2つのさらなる置換基である。カルバモイル部分はその保護誘導体を含んでいてもよいことに注意する。カルバモイル部分の適切な保護基の例としては、アセチル、tert-ブトキシカルボニル、ベンジルオキシカルボニルなどが挙げられる。非保護及び保護誘導体の両方が本発明の範囲内に含まれることに注意する。 "Carbamoyl" refers to the group -OC(O)NR a R b , where R a and R b are each independently two further substituents where a hydrogen or a carbon atom is alpha to the nitrogen. It is noted that the carbamoyl moiety may include protected derivatives thereof. Examples of suitable protecting groups for the carbamoyl moiety include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like. It is noted that both unprotected and protected derivatives are included within the scope of the present invention.
「カルボニル」は、-C(O)-基を意味する。カルボニル基を様々な置換基でさらに置換して、酸、酸ハロゲン化物、アミド、エステル、及びケトンを含めた様々なカルボニル基を形成させてもよいことに注意する。 "Carbonyl" refers to the -C(O)- group. It is noted that the carbonyl group may be further substituted with a variety of substituents to form different carbonyl groups including acids, acid halides, amides, esters, and ketones.
「カルボキシ」は、-C(O)O-基を意味する。カルボキシ部分を含有する本発明の化合物は、その保護誘導体、すなわち酸素が保護基で置換されている保護誘導体を含んでいてもよいことに注意する。カルボキシ部分の適切な保護基としては、ベンジル、tert-ブチルなどが挙げられる。 "Carboxy" refers to the -C(O)O- group. It is noted that compounds of the invention that contain a carboxy moiety may include protected derivatives thereof, i.e., where the oxygen is replaced with a protecting group. Suitable protecting groups for the carboxy moiety include benzyl, tert-butyl, and the like.
「シアノ」は、-CN基を意味する。 "Cyano" refers to the -CN group.
「ホルミル」は、-CH=O基を意味する。 "Formyl" refers to the -CH=O group.
「ホルムイミノ」は、-HC=NH基を意味する。 "Formimino" refers to the -HC=NH group.
「ハロ」は、フルオロ、クロロ、ブロモ、又はヨードを意味する。 "Halo" means fluoro, chloro, bromo, or iodo.
単独の基として又はより大きい基の一部としての、「ハロ置換アルキル」は、1つ以上の「ハロ」原子で置換された「アルキル」を意味し、そのように用語はこの出願で定義される。ハロ置換アルキルとしては、ハロアルキル、ジハロアルキル、トリハロアルキル、ペルハロアルキルなどが挙げられる。 "Halo-substituted alkyl," as a single group or part of a larger group, means an "alkyl" substituted with one or more "halo" atoms, as that term is defined in this application. Halo-substituted alkyls include haloalkyls, dihaloalkyls, trihaloalkyls, perhaloalkyls, and the like.
「ヒドロキシ」は、-OH基を意味する。 "Hydroxy" means the -OH group.
「イミン誘導体」は、-C(=NR)-部分を含む誘導体を意味し、式中、Rは窒素に対してアルファ位である水素又は炭素原子を含む。 "Imine derivative" means a derivative containing a -C(=NR)- moiety, where R contains a hydrogen or carbon atom alpha to the nitrogen.
「異性体」は、同一の分子式を有するが、性質、又はそれらの原子の結合の配列、又は空間内でのそれらの原子の配置が異なる、任意の化合物を意味する。空間内でのそれらの原子の配置が異なる異性体は「立体異性体」と呼ばれる。互いの鏡像ではない立体異性体は「ジアステレオマー」と呼ばれ、重ね合せできることができない鏡像である立体異性体は「エナンチオマー」、又は場合により「光学異性体」と呼ばれる。4つの同一ではない置換基に結合している炭素原子は「キラル中心」と呼ばれる。1つのキラル中心を有する化合物は、反対のキラリティの2つのエナンチオマー型を有する。2つのエナンチオマー型の混合物は「ラセミ混合物」と呼ばれる。 "Isomers" means any compounds that have identical molecular formulae but differ in the properties or the sequence of bonds of their atoms or the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are called "stereoisomers". Stereoisomers that are not mirror images of one another are called "diastereomers" and stereoisomers that are non-superimposable mirror images are called "enantiomers" or sometimes "optical isomers". A carbon atom that is bonded to four non-identical substituents is called a "chiral center". A compound with one chiral center has two enantiomeric forms of opposite chirality. A mixture of the two enantiomeric forms is called a "racemic mixture".
「ニトロ」は、-NO2基を意味する。 "Nitro" refers to the -NO2 group.
「保護誘導体」は、反応性部位が保護基でブロックされている、化合物の誘導体を意味する。保護誘導体は、医薬の調製において有用であり、又はそれ自体で阻害剤として活性である場合もある。適切な保護基の全リストはT.W.Greene、Protecting Groups in Organic Synthesis、第3版、Wiley & Sons、1999年において見ることができる。 "Protected derivatives" means derivatives of compounds in which reactive sites are blocked with protecting groups. Protected derivatives may be useful in the preparation of pharmaceuticals or may be active as inhibitors themselves. A complete list of suitable protecting groups can be found in T.W. Greene, Protecting Groups in Organic Synthesis, 3rd Edition, Wiley & Sons, 1999.
「置換」という用語は、原子又は原子のグループが、別の基に結合している置換基として水素と置き換わっていることを意味する。アリール及びヘテロアリール基については、「置換」という用語は、任意のレベルの置換が可能である場合、任意のレベルの置換、すなわちモノ-、ジ-、トリ-、テトラ-、又はペンタ-置換を指す。置換基は独立に選択され、置換は任意の化学的に利用可能な位置で行われてもよい。「非置換」という用語は、所与の部分が利用可能な結合価の全体で水素置換基のみから成り得る(非置換)ことを意味する。 The term "substituted" means that an atom or group of atoms replaces hydrogen as a substituent bonded to another group. For aryl and heteroaryl groups, the term "substituted" refers to any level of substitution, i.e., mono-, di-, tri-, tetra-, or penta-substitution, where such levels are possible. The substituents are independently selected, and substitution may occur at any chemically available position. The term "unsubstituted" means that a given moiety may consist of only hydrogen substituents (unsubstituted) across all available valences.
官能基が「場合により置換されている」と記載されている場合、官能基は、(1)非置換であってもよく、又は(2)置換されていてもよい。官能基の炭素が置換基のリストの1つ以上で場合により置換されていると記載されている場合、炭素上の水素原子の1つ以上が(水素原子が存在する範囲内で)別々に及び/又は共に、独立に選択された任意選択の置換基で置き換えられていてもよい。 When a functional group is described as "optionally substituted," the functional group may be (1) unsubstituted or (2) substituted. When a carbon of a functional group is described as being optionally substituted with one or more of a list of substituents, one or more of the hydrogen atoms on the carbon may be replaced separately and/or together (to the extent that hydrogen atoms are present) with an independently selected optional substituent.
「スルフィド」は、-S-Rを意味し、式中、RはH、アルキル、炭素環、複素環、カルボシクロアルキル、又はヘテロシクロアルキルである。具体的なスルフィド基は、メルカプト、アルキルスルフィド、例えばメチルスルフィド(-S-Me); アリールスルフィド、例えば、フェニルスルフィド;アラルキルスルフィド、例えば、ベンジルスルフィドである。 "Sulfide" means -S-R, where R is H, alkyl, carbocycle, heterocycle, carbocycloalkyl, or heterocycloalkyl. Particular sulfide groups are mercapto, alkyl sulfides, such as methyl sulfide (-S-Me); aryl sulfides, such as phenyl sulfide; aralkyl sulfides, such as benzyl sulfide.
「スルフィニル」は、-S(O)-基を意味する。スルフィニル基を様々な置換基でさらに置換して、スルフィン酸、スルフィンアミド、スルフィニルエステル、及びスルホキシドを含めた、様々なスルフィニル基を得ることができることに注意する。 "Sulfinyl" refers to the group -S(O)-. It is noted that the sulfinyl group can be further substituted with a variety of substituents to give different sulfinyl groups including sulfinic acids, sulfinamides, sulfinyl esters, and sulfoxides.
「スルホニル」は、-S(O)(O)-基を意味する。スルホニル基を様々な置換基でさらに置換して、スルホン酸、スルホンアミド、スルホン酸エステル、及びスルホンを含めた、様々なスルホニル基を得ることができることに注意する。 "Sulfonyl" refers to the group -S(O)(O)-. It is noted that the sulfonyl group can be further substituted with a variety of substituents to give different sulfonyl groups including sulfonic acids, sulfonamides, sulfonate esters, and sulfones.
「チオカルボニル」は、-C(S)-基を意味する。チオカルボニル基を様々な置換基でさらに置換して、チオ酸、チオアミド、チオエステル、及びチオケトンを含めた、様々なチオカルボニル基を得ることができることに注意する。 "Thiocarbonyl" refers to the -C(S)- group. It is noted that the thiocarbonyl group can be further substituted with a variety of substituents to give different thiocarbonyl groups, including thioacids, thioamides, thioesters, and thioketones.
「動物」は、ヒト、非ヒト哺乳類(例えば、非ヒト霊長類、げっ歯類、マウス、ラット、ハムスター、イヌ、ネコ、ウサギ、ウシ、ウマ、ヒツジ、ヤギ、ブタ、シカなど)、及び非哺乳類(例えば、トリなど)を含む。 "Animal" includes humans, non-human mammals (e.g., non-human primates, rodents, mice, rats, hamsters, dogs, cats, rabbits, cows, horses, sheep, goats, pigs, deer, etc.), and non-mammals (e.g., birds, etc.).
本明細書で使用する「バイオアベイラビリティ」は、損なわれずに体循環に到達する、薬物又は医薬組成物の投与量の分率又はパーセンテージである。一般に、薬が静脈内に投与される場合、そのバイオアベイラビリティは100%である。しかし、薬が他の経路を介して(例えば、経口)投与される場合、そのバイオアベイラビリティは低下する(例えば、不完全な吸収及び初回通過代謝に起因して)。バイオアベイラビリティを改善する方法としては、プロドラッグ法、塩合成、粒径の減少、複合体形成、物理的形態の変化、固体分散物、噴霧乾燥、及び熱間溶融押出しが挙げられる。 As used herein, "bioavailability" is the fraction or percentage of a dose of a drug or pharmaceutical composition that reaches the systemic circulation intact. Generally, when a drug is administered intravenously, its bioavailability is 100%. However, when a drug is administered via other routes (e.g., orally), its bioavailability is reduced (e.g., due to incomplete absorption and first-pass metabolism). Methods to improve bioavailability include prodrug techniques, salt synthesis, particle size reduction, complexation, physical form changes, solid dispersions, spray drying, and hot melt extrusion.
「疾患」は、具体的には動物又はその一部の任意の不健康な状態を含み、その動物に施された医学療法又は獣医学療法によって引き起こされることがある、又はそれに付随することがある、不健康な状態、すなわちそのような療法の「副作用」を含む。 "Disease" specifically includes any unhealthy condition of an animal or part thereof, including an unhealthy condition that may be caused by or that may accompany a medical or veterinary therapy administered to the animal, i.e. a "side effect" of such therapy.
「薬学的に許容可能な」とは、一般に安全で非毒性であり、生物学的にもその他の点でも好ましくないものではない、医薬組成物の調製において有用であることを意味し、獣医学的使用並びにヒトの医薬への使用において許容可能であることを含む。 "Pharmaceutically acceptable" means generally safe, non-toxic, not biologically or otherwise objectionable, and useful in the preparation of pharmaceutical compositions, including acceptable for veterinary use as well as for use in human medicine.
「薬学的に許容可能な塩」とは、上記で定義されるように薬学的に許容可能であり、所望の薬理学的活性を有する、本発明の化合物の有機又は無機塩を意味する。そのような塩としては、無機酸、又は有機酸で形成される酸付加塩が挙げられる。薬学的に許容可能な塩としては、存在する酸性プロトンが無機又は有機塩基と反応することが可能である場合に形成させることができる、塩基付加塩も挙げられる。例示的な塩としては、限定はされないが、硫酸塩、クエン酸塩、酢酸塩、シュウ酸塩、塩化物、臭化物、ヨウ化物、硝酸塩、重硫酸塩、リン酸塩、酸性リン酸塩、イソニコチン酸塩、乳酸塩、サリチル酸塩、酸性クエン酸塩、酒石酸塩、オレイン酸塩、タンニン酸塩、パントテン酸塩、酒石酸水素塩、アスコルビン酸塩、コハク酸塩、マレイン酸塩、ゲンチジン酸塩、フマル酸塩、グルコン酸塩、グルクロン酸塩、サッカリン酸塩、ギ酸塩、安息香酸塩、グルタミン酸塩、メタンスルホン酸塩「メシル酸塩」、エタンスルホン酸塩、ベンゼンスルホン酸塩、p-トルエンスルホン酸塩、パモ酸塩(すなわち、1,1'-メチレン-ビス-(2-ヒドロキシ-3-ナフトエート))塩、アルカリ金属(例えば、ナトリウム及びカリウム)塩、アルカリ土類金属(例えば、マグネシウム)塩、並びにアンモニウム塩が挙げられる。薬学的に許容可能な塩は、酢酸イオン、コハク酸イオン、又は他の対イオンなどの、別の分子の含有物を含むことがある。対イオンは、親化合物上の電荷を安定化させる任意の有機又は無機部分であってもよい。さらに、薬学的に許容可能な塩は、その構造中に1つを超える荷電原子を有していてもよい。複数の荷電原子が薬学的に許容可能な塩の一部である例は、複数の対イオンを有することがある。したがって、薬学的に許容可能な塩は、1つ以上の荷電原子及び/又は1つ以上の対イオンを有していてもよい。 "Pharmaceutically acceptable salt" means an organic or inorganic salt of a compound of the present invention that is pharma- ceutically acceptable as defined above and has the desired pharmacological activity. Such salts include acid addition salts formed with inorganic or organic acids. Pharmaceutically acceptable salts also include base addition salts that can be formed when acidic protons present are capable of reacting with inorganic or organic bases. Exemplary salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate "mesylate", ethanesulfonate, benzenesulfonate, p-toluenesulfonate, pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts, alkali metal (e.g., sodium and potassium) salts, alkaline earth metal (e.g., magnesium) salts, and ammonium salts. A pharma- ceutically acceptable salt may include the inclusion of another molecule, such as an acetate ion, a succinate ion, or other counterion. The counterion may be any organic or inorganic moiety that stabilizes the charge on the parent compound. Additionally, a pharma- ceutically acceptable salt may have more than one charged atom in its structure. Instances in which multiple charged atoms are part of a pharma- ceutically acceptable salt may have multiple counterions. Thus, a pharma- ceutically acceptable salt may have one or more charged atoms and/or one or more counterions.
国際純正・応用化学連合により定義される「ファーマコフォア」は、特定の生物学的標的との最適な超分子相互作用を確実にするため及びその生物学的応答を引き起こす(又はブロックする)ために必要である、立体的特徴及び電子的特徴の全体的効果である。例えば、カンプトテシンは、良く知られている薬物であるトポテカン及びイリノテカンのファーマコフォアである。メクロレタミンは、メルファラン、シクロホスファミド、ベンダムスチンなどのような、広く使用されるナイトロジェンマスタード薬物のリストのファーマコフォアである。 A "pharmacophore," as defined by the International Union of Pure and Applied Chemistry, is the total effect of steric and electronic features necessary to ensure optimal supramolecular interaction with a particular biological target and to trigger (or block) its biological response. For example, camptothecin is the pharmacophore of the well-known drugs topotecan and irinotecan. Mechlorethamine is the pharmacophore of a list of widely used nitrogen mustard drugs, such as melphalan, cyclophosphamide, bendamustine, etc.
「プロドラッグ」とは、インビボで代謝により、本発明による活性医薬へ転化可能である化合物を意味する。例えば、ヒドロキシル基を含む阻害剤は、インビボで加水分解によりヒドロキシル化合物へ転化されるエステルとして投与することができる。 "Prodrug" means a compound that is convertible in vivo by metabolism to an active pharmaceutical agent according to the present invention. For example, an inhibitor that contains a hydroxyl group can be administered as an ester that is converted to the hydroxyl compound by hydrolysis in vivo.
「安定性」は一般的に、薬物が効能を失わずにその特性を保持する時間の長さを指す。これは保存期間と呼ばれることもある。薬物の安定性に影響を与える要因としては、とりわけ、薬物の化学構造、製剤中の不純物、pH、水分含量、並びに環境的要因、例えば温度、酸化、光、及び相対湿度などが挙げられる。適切な化学修飾及び/又は結晶改質(例えば、水和の反応速度を変化させることができる表面改質;異なる特性を有することができる異なる結晶)、賦形剤(例えば、剤形中の活性物質以外のもの)、包装条件、保存条件などを提供することにより、安定性を改善することができる。 "Stability" generally refers to the length of time that a drug retains its properties without losing efficacy. This is sometimes called shelf life. Factors that affect drug stability include, among others, the chemical structure of the drug, impurities in the formulation, pH, moisture content, and environmental factors such as temperature, oxidation, light, and relative humidity. Stability can be improved by providing appropriate chemical and/or crystal modifications (e.g., surface modifications that can change the kinetics of hydration; different crystals that can have different properties), excipients (e.g., other than the active substance in the dosage form), packaging conditions, storage conditions, etc.
本明細書に記載の組成物の「治療有効量」とは、任意の医療に適用可能な妥当なベネフィット/リスク比で、治療される対象に対して治療効果を与える組成物の量を意味する。治療効果は、客観的(すなわち、何らかの試験又はマーカーによって測定可能である)又は主観的(すなわち、対象が効果の兆候又は感覚を示す)であってもよい。上記の組成物の有効量は、約0.1mg/kg~約500mg/kg、好ましくは約0.2~約50mg/kgの範囲であってもよい。有効用量はまた、投与の経路、並びに他の薬剤との併用の可能性に応じて変動する。しかし、本発明の組成物の総合的な日常使用は、担当医によって健全な医学的判断の範囲内で決定されることが、理解される。任意の特定の患者についての具体的な治療上有効な用量レベルは、治療されている病気及び病気の重篤度;採用される特定の化合物の活性;採用される特定の組成物;患者の年齢、体重、全般的健康状態、性別、及び食事;採用される特定の化合物の投与の時間、投与の経路、及び排出の速度;治療の期間;採用される特定の化合物と組み合わせて又は同時に使用される薬物;並びに医療の技術分野で良く知られている同様の要因を含めた、様々な要因に応じて決まる。 A "therapeutically effective amount" of a composition described herein means an amount of the composition that confers a therapeutic effect on the treated subject at a reasonable benefit/risk ratio applicable to any medical treatment. The therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., the subject shows signs or feels an effect). An effective amount of the composition may range from about 0.1 mg/kg to about 500 mg/kg, preferably about 0.2 to about 50 mg/kg. Effective doses will also vary depending on the route of administration, as well as the possibility of co-administration with other drugs. However, it will be understood that the overall daily use of the compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend on a variety of factors, including the disease and severity of the disease being treated; the activity of the particular compound employed; the particular composition employed; the patient's age, weight, general health, sex, and diet; the time of administration, route of administration, and rate of excretion of the particular compound employed; the duration of treatment; drugs used in combination or concomitantly with the particular compound employed; and similar factors well known in the medical arts.
本明細書で使用する、「治療」という用語は、病気、病気の症状又は病気への素因を取り除く、治癒する、緩和する、軽減する、改変する、矯正する、改良する、改善する、又は作用する目的で、新生物性の病気若しくは免疫性の病気を有する、或いは新生物性の病気若しくは免疫性の病気の症状又は新生物性の病気若しくは免疫性の病気への素因を有する対象へ化合物を投与することを指す。「有効量」という用語は、対象において意図する治療効果を与えるのに必要とされる活性剤の量を指す。有効量は、当業者により認識されるように、投与の経路、賦形剤の使用、他の薬剤との併用の可能性に応じて変動する場合がある。 As used herein, the term "treatment" refers to the administration of a compound to a subject having a neoplastic or immune disease, or a symptom of a neoplastic or immune disease, or a predisposition to a neoplastic or immune disease, for the purpose of eliminating, curing, alleviating, mitigating, altering, correcting, ameliorating, improving, or affecting a disease, a symptom of a disease, or a predisposition to a disease. The term "effective amount" refers to the amount of active agent required to provide the intended therapeutic effect in a subject. Effective amounts may vary depending on the route of administration, the use of excipients, and the possibility of co-use with other drugs, as will be recognized by those skilled in the art.
「対象」とは、ヒト及び非ヒト動物を指す。非ヒト動物の例としては、あらゆる脊椎動物、例えば、哺乳類、例えば非ヒト霊長類(特に高等霊長類)、イヌ、げっ歯類(例えば、マウス又はラット)、モルモット、ネコ、及び非哺乳類、例えば、トリ、両生類、爬虫類などが挙げられる。好ましい実施形態において、対象はヒトである。別の実施形態において、対象は、実験動物、又は疾患モデルとして適した動物である。 "Subject" refers to humans and non-human animals. Examples of non-human animals include any vertebrate, e.g., mammals, such as non-human primates (especially higher primates), dogs, rodents (e.g., mice or rats), guinea pigs, cats, and non-mammals, such as birds, amphibians, reptiles, etc. In a preferred embodiment, the subject is a human. In another embodiment, the subject is an experimental animal or an animal suitable as a disease model.
「併用療法」は、他の生物学的活性成分(限定はされないが、第2の及び異なる抗悪性腫瘍剤など)及び非薬物療法(限定はされないが、手術又は放射線治療など)とさらに組み合わせて、本発明の対象化合物を投与することを含む。例えば、本発明の化合物は、他の薬学的に活性な化合物、又は非薬物療法、好ましくは本発明の化合物の効果を向上することができる化合物と組み合わせて使用することができる。本発明の化合物は、他の療法と同時に(単一の調剤又は別々の調剤として)又は順次に投与することができる。一般に、併用療法は、療法の1回のサイクルの間又は療法の過程で2種以上の薬物/治療の投与を想定している。 "Combination therapy" includes administration of the subject compounds of the present invention in further combination with other biologically active ingredients (such as, but not limited to, a second and different anti-neoplastic agent) and non-pharmacological therapies (such as, but not limited to, surgery or radiation therapy). For example, the compounds of the present invention can be used in combination with other pharmacologic active compounds, or non-pharmacological therapies, preferably compounds that can enhance the effect of the compounds of the present invention. The compounds of the present invention can be administered simultaneously (as a single formulation or separate formulations) or sequentially with the other therapies. In general, combination therapy contemplates administration of two or more drugs/treatments during one cycle or course of therapy.
一実施形態において、本発明の化合物は、従来の化学療法剤の1つ以上と組み合わせて投与される。従来の化学療法剤は、オンコロジーの分野において広範囲な治療的処置を包含する。これらの薬剤は、疾患の様々な段階で、腫瘍を収縮させる、手術後に残存する残りの癌細胞を破壊する、緩解を誘発する、緩解を維持する及び/又は癌又はその治療に関係する症状を緩和する目的のために投与される。そのような薬剤の例としては、限定はされないが、アルキル化剤、例えば、ナイトロジェンマスタード(例えば、ベンダムスチン、シクロホスファミド、メルファラン、クロラムブシル、イソホスファミド)、ニトロソウレア(例えば、カルムスチン、ロムスチン及びストレプトゾシン)、エチレンイミン(例えば、チオテパ、ヘキサメチルメラニン)、アルキルスルホネート(例えば、ブスルファン)、ヒドラジン及びトリアジン(例えば、アルトレタミン、プロカルバジン、ダカルバジン及びテモゾロミド)、及び白金ベースの薬剤(例えば、カルボプラチン、シスプラチン、及びオキサリプラチン);植物アルカロイド、例えば、ポドフィロトキシン(例えば、エトポシド及びテニポシド)、タキサン(例えば、パクリタキセル及びドセタキセル)、ビンカアルカロイド(例えば、ビンクリスチン、ビンブラスチン及びビノレルビン);抗腫瘍抗生剤、例えば、クロモマイシン(例えば、ダクチノマイシン及びプリカマイシン)、アントラサイクリン(例えば、ドキソルビシン、ダウノルビシン、エピルビシン、ミトキサントロン、及びイダルビシン)、及び様々な抗生剤、例えば、マイトマイシン及びブレオマイシン;代謝拮抗剤、例えば、葉酸アンタゴニスト(例えば、メトトレキセート)、ピリミジンアンタゴニスト(例えば、5-フルオロウラシル、フロクスウリジン、シタラビン、カペシタビン、及びゲムシタビン)、プリンアンタゴニスト(例えば、6-メルカプトプリン及び6-チオグアニン)及びアデノシンデアミナーゼ阻害剤(例えば、クラドリビン、フルダラビン、ネララビン及びペントスタチン);トポイソメラーゼ阻害剤、例えば、トポイソメラーゼI阻害剤(トポテカン、イリノテカン)、トポイソメラーゼII阻害剤(例えば、アムサクリン、エトポシド、リン酸エトポシド、テニポシド)、並びに様々な抗新生物薬、例えば、リボヌクレオチド還元酵素阻害剤(ヒドロキシウレア)、副腎皮質ステロイド阻害剤(ミトタン)、抗微小管剤(エストラムスチン)、及びレチノイド(ベキサロテン、イソトレチノイン、トレチノイン(ATRA)が挙げられる。 In one embodiment, the compounds of the present invention are administered in combination with one or more conventional chemotherapeutic agents. Conventional chemotherapeutic agents encompass a broad range of therapeutic treatments in the field of oncology. These agents are administered at various stages of the disease for the purpose of shrinking tumors, destroying residual cancer cells remaining after surgery, inducing remission, maintaining remission, and/or alleviating symptoms related to cancer or its treatment. Examples of such agents include, but are not limited to, alkylating agents such as nitrogen mustards (e.g., bendamustine, cyclophosphamide, melphalan, chlorambucil, isophosphamide), nitrosoureas (e.g., carmustine, lomustine, and streptozocin), ethylenimines (e.g., thiotepa, hexamethylmelanin), alkylsulfonates (e.g., busulfan), hydrazines and triazines (e.g., altretamine, procarbazine, dacarbazine, and tetroxin), and the like. mozolomide), and platinum-based agents (e.g., carboplatin, cisplatin, and oxaliplatin); plant alkaloids, such as podophyllotoxins (e.g., etoposide and teniposide), taxanes (e.g., paclitaxel and docetaxel), vinca alkaloids (e.g., vincristine, vinblastine, and vinorelbine); antitumor antibiotics, such as chromomycins (e.g., dactinomycin and plicamycin), anthracyclines (e.g., doxorubicin, daunorubicin, anti-inflammatory drugs such as cyclosporine, epirubicin, mitoxantrone, and idarubicin, and various antibiotics such as mitomycin and bleomycin; antimetabolites such as folate antagonists (e.g., methotrexate), pyrimidine antagonists (e.g., 5-fluorouracil, floxuridine, cytarabine, capecitabine, and gemcitabine), purine antagonists (e.g., 6-mercaptopurine and 6-thioguanine), and adenosine deaminase inhibitors (e.g., cladribine, fludarabine, nera, rabine and pentostatin; topoisomerase inhibitors such as topoisomerase I inhibitors (topotecan, irinotecan), topoisomerase II inhibitors (e.g., amsacrine, etoposide, etoposide phosphate, teniposide), and various antineoplastic agents such as ribonucleotide reductase inhibitors (hydroxyurea), corticosteroid inhibitors (mitotane), anti-microtubule agents (estramustine), and retinoids (bexarotene, isotretinoin, tretinoin (ATRA)).
本発明の一態様において、化合物は、様々な病態に関与しているタンパク質キナーゼをモジュレートする1種以上の標的抗癌剤と組み合わせて投与することができる。そのようなキナーゼの例としては、これらに限定はされないがABL1、ABL2/ARG、ACK1、AKT1、AKT2、AKT3、ALK、ALK1/ACVRL1、ALK2/ACVR1、ALK4/ACVR1B、ALK5/TGFBR1、ALK6/BMPR1B、AMPK(A1/B1/G1)、AMPK(A1/B1/G2)、AMPK(A1/B1/G3)、AMPK(A1/B2/G1)、AMPK(A2/B1/G1)、AMPK(A2/B2/G1)、AMPK(A2/B2/G2)、ARAF、ARK5/NUAK1、ASK1/MAP3K5、ATM、Aurora A、Aurora B、Aurora C、AXL、BLK、BMPR2、BMX/ETK、BRAF、BRK、BRSK1、BRSK2、BTK、CAMK1a、CAMK1b、CAMK1d、CAMK1g、CAMKIIa、CAMKIIb、CAMKIId、CAMKIIg、CAMK4、CAMKK1、CAMKK2、CDC7-DBF4、CDK1-サイクリンA、CDK1-サイクリンB、CDK1-サイクリンE、CDK2-サイクリンA、CDK2-サイクリンA1、CDK2-サイクリンE、CDK3-サイクリンE、CDK4-サイクリンD1、CDK4-サイクリンD3、CDK5-p25、CDK5-p35、CDK6-サイクリンD1、CDK6-サイクリンD3、CDK7-サイクリンH、CDK9-サイクリンK、CDK9-サイクリンT1、CHK1、CHK2、CK1a1、CK1d、CK1epsilon、CK1g1、CK1g2、CK1g3、CK2a、CK2a2、c-KIT、CLK1、CLK2、CLK3、CLK4、c-MER、c-MET、COT1/MAP3K8、CSK、c-SRC、CSF1R、CTK/MATK、DAPK1、DAPK2、DCAMKL1、DCAMKL2、DDR1、DDR2、DLK/MAP3K12、DMPK、DMPK2/CDC42BPG、DNA-PK、DRAK1/STK17A、DYRK1/DYRK1A、DYRK1B、DYRK2、DYRK3、DYRK4、EEF2K、EGFR、EIF2AK1、EIF2AK2、EIF2AK3、EIF2AK4/GCN2、EPHA1、EPHA2、EPHA3、EPHA4、EPHA5、EPHA6、EPHA7、EPHA8、EPHB1、EPHB2、EPHB3、EPHB4、ERBB2/HER2、ERBB4/HER4、ERK1/MAPK3、ERK2/MAPK1、ERK5/MAPK7、FAK/PTK2、FER、FES/FPS、FGFR1、FGFR2、FGFR3、FGFR4、FGR、FLT1/VEGFR1、FLT3、FLT4/VEGFR3、FMS、FRK/PTK5、FYN、GCK/MAP4K2、GRK1、GRK2、GRK3、GRK4、GRK5、GRK6、GRK7、GSK3a、GSK3b、Haspin、HCK、HGK/MAP4K4、HIPK1、HIPK2、HIPK3、HIPK4、HPK1/MAP4K1、IGF1R、IKKa/CHUK、IKKb/IKBKB、IKKe/IKBKE、IR、IRAK1、IRAK4、IRR/INSRR、ITK、JAK1、JAK2、JAK3、JNK1、JNK2、JNK3、KDR/VEGFR2、KHS/MAP4K5、LATS1、LATS2、LCK、LCK2/ICK、LKB1、LIMK1、LOK/STK10、LRRK2、LYN、LYNB、MAPKAPK2、MAPKAPK3、MAPKAPK5/PRAK、MARK1、MARK2/PAR-1Ba、MARK3、MARK4、MEK1、MEK2、MEKK1、MEKK2、MEKK3、MELK、MINK/MINK1、MKK4、MKK6、MLCK/MYLK、MLCK2/MYLK2、MLK1/MAP3K9、MLK2/MAP3K10、MLK3/MAP3K11、MNK1、MNK2、MRCKa/、CDC42BPA、MRCKb/、CDC42BPB、MSK1/RPS6KA5、MSK2/RPS6KA4、MSSK1/STK23、MST1/STK4、MST2/STK3、MST3/STK24、MST4、mTOR/FRAP1、MUSK、MYLK3、MYO3b、NEK1、NEK2、NEK3、NEK4、NEK6、NEK7、NEK9、NEK11、NIK/MAP3K14、NLK、OSR1/OXSR1、P38a/MAPK14、P38b/MAPK11、P38d/MAPK13、P38g/MAPK12、P70S6K/RPS6KB1、p70S6Kb/、RPS6KB2、PAK1、PAK2、PAK3、PAK4、PAK5、PAK6、PASK、PBK/TOPK、PDGFRa、PDGFRb、PDK1/PDPK1、PDK1/PDHK1、PDK2/PDHK2、PDK3/PDHK3、PDK4/PDHK4、PHKg1、PHKg2、PI3Ka、(p110a/p85a)、PI3Kb、(p110b/p85a)、PI3Kd、(p110d/p85a)、PI3Kg(p120g)、PIM1、PIM2、PIM3、PKA、PKAcb、PKAcg、PKCa、PKCb1、PKCb2、PKCd、PKCepsilon、PKCeta、PKCg、PKCiota、PKCmu/PRKD1、PKCnu/PRKD3、PKCtheta、PKCzeta、PKD2/PRKD2、PKG1a、PKG1b、PKG2/PRKG2、PKN1/PRK1、PKN2/PRK2、PKN3/PRK3、PLK1、PLK2、PLK3、PLK4/SAK、PRKX、PYK2、RAF1、RET、RIPK2、RIPK3、RIPK5、ROCK1、ROCK2、RON/MST1R、ROS/ROS1、RSK1、RSK2、RSK3、RSK4、SGK1、SGK2、SGK3/SGKL、SIK1、SIK2、SLK/STK2、SNARK/NUAK2、SRMS、SSTK/TSSK6、STK16、STK22D/TSSK1、STK25/YSK1、STK32b/YANK2、STK32c/YANK3、STK33、STK38/NDR1、STK38L/NDR2、STK39/STLK3、SRPK1、SRPK2、SYK、TAK1、TAOK1、TAOK2/TAO1、TAOK3/JIK、TBK1、TEC、TESK1、TGFBR2、TIE2/TEK、TLK1、TLK2、TNIK、TNK1、TRKA、TRKB、TRKC、TRPM7/CHAK1、TSSK2、TSSK3/STK22C、TTBK1、TTBK2、TTK、TXK、TYK1/LTK、TYK2、TYRO3/SKY、ULK1、ULK2、ULK3、VRK1、VRK2、WEE1、WNK1、WNK2、WNK3、YES/YES1、ZAK/MLTK、ZAP70、ZIPK/DAPK3、KINASE、MUTANTS、ABL1(E255K)、ABL1(F317I)、ABL1(G250E)、ABL1(H396P)、ABL1(M351T)、ABL1(Q252H)、ABL1(T315I)、ABL1(Y253F)、ALK(C1156Y)、ALK(L1196M)、ALK(F1174L)、ALK(R1275Q)、BRAF(V599E)、BTK(E41K)、CHK2(I157T)、c-Kit(A829P)、c-KIT(D816H)、c-KIT(D816V)、c-Kit(D820E)、c-Kit(N822K)、C-Kit(T670I)、c-Kit(V559D)、c-Kit(V559D/V654A)、c-Kit(V559D/T670I)、C-Kit(V560G)、c-KIT(V654A)、C-MET(D1228H)、C-MET(D1228N)、C-MET(F1200I)、c-MET(M1250T)、C-MET(Y1230A)、C-MET(Y1230C)、C-MET(Y1230D)、C-MET(Y1230H)、c-Src(T341M)、EGFR(G719C)、EGFR(G719S)、EGFR(L858R)、EGFR(L861Q)、EGFR(T790M)、EGFR、(L858R、T790M)、EGFR(d746-750/T790M)、EGFR(d746-750)、EGFR(d747-749/A750P)、EGFR(d747-752/P753S)、EGFR(d752-759)、FGFR1(V561M)、FGFR2(N549H)、FGFR3(G697C)、FGFR3(K650E)、FGFR3(K650M)、FGFR4(N535K)、FGFR4(V550E)、FGFR4(V550L)、FLT3(D835Y)、FLT3(ITD)、JAK2(V617F)、LRRK2(G2019S)、LRRK2(I2020T)、LRRK2(R1441C)、p38a(T106M)、PDGFRa(D842V)、PDGFRa(T674I)、PDGFRa(V561D)、RET(E762Q)、RET(G691S)、RET(M918T)、RET(R749T)、RET(R813Q)、RET(V804L)、RET(V804M)、RET(Y791F)、TIF2(R849W)、TIF2(Y897S)、及びTIF2(Y1108F)を挙げることができる。 In one embodiment of the invention, the compounds can be administered in combination with one or more targeted anti-cancer agents that modulate protein kinases involved in various disease states. Examples of such kinases include, but are not limited to, ABL1, ABL2/ARG, ACK1, AKT1, AKT2, AKT3, ALK, ALK1/ACVRL1, ALK2/ACVR1, ALK4/ACVR1B, ALK5/TGFBR1, ALK6/BMPR1B, AMPK(A1/B1/G1), AMPK(A1/B1/G2), AMPK(A1/B1/G3), AMPK(A1/B2/G1), AMPK(A2/B1/G1), AMPK(A2/B2/G1), AMPK(A2/B2/G2), ARAF, ARK5/NUAK1, ASK1/MAP3K5, ATM, Aurora A, Aurora B, Aurora C, Aurora D, Aurora E, Aurora F ... C, AXL, BLK, BMPR2, BMX/ETK, BRAF, BRK, BRSK1, BRSK2, BTK, CAMK1a, CAMK1b, CAMK1d, CAMK1g, CAMKIIa, CAMKIIb, CAMKIId, CAMKIIg, CAMK4, CAMKK1, CAMKK2, CDC7-DBF4, CDK1-cyclin A, CDK1-cyclin B, CDK1-cyclin E, CDK2-cyclin A, CDK2-cyclin A1, CDK2-cyclin E, CDK3-cyclin E , CDK4-cyclin D1, CDK4-cyclin D3, CDK5-p25, CDK5-p35, CDK6-cyclin D1, CDK6-cyclin D3, CDK7-cyclin H, CDK9-cyclin K, CDK9-cyclin T1, CHK1, CHK2, CK1a1, CK1d, CK1epsilon, CK1g1, CK1g2, CK1g3, CK2a, CK2a2, c-KIT, CLK1, CLK2, CLK3, CLK4, c-MER, c-MET, COT1/MAP3K8, CSK, c -SRC, CSF1R, CTK/MATK, DAPK1, DAPK2, DCAMKL1, DCAMKL2, DDR1, DDR2, DLK/MAP3K12, DMPK, DMPK2/CDC42BPG, DNA-PK, DRAK1/STK17A, DYRK1/DYRK1A, DYRK1B, DYRK2, DYRK3, DYRK4, EEF2K, EGFR, EIF2AK1, EIF2AK2, EIF2AK3, EIF2AK4/GCN2, EPHA1, EPHA2, EPHA3, EPHA4, EPH A5, EPHA6, EPHA7, EPHA8, EPHB1, EPHB2, EPHB3, EPHB4, ERBB2/HER2, ERBB4/HER4, ERK1/MAPK3, ERK2/MAPK1, ERK5/MAPK7, FAK/PTK2, FER, FES/FPS, FGFR1, FGFR2, FGFR3, FGFR4, FGR, FLT1/VEGFR1, FLT3, FLT4/VEGFR3, FMS, FRK/PTK5, FYN, GCK/MAP4K2, GRK1, GRK2, GRK3, GRK 4, GRK5, GRK6, GRK7, GSK3a, GSK3b, Haspin, HCK, HGK/MAP4K4, HIPK1, HIPK2, HIPK3, HIPK4, HPK1/MAP4K1, IGF1R, IKKa/CHUK, IKKb/IKBKB, IKKe/IKBKE, IR, IRAK1, IRAK4, IRR/INSRR, ITK, JAK1, JAK2, JAK3, JNK1, JNK2, JNK3, KDR/VEGFR2, KHS/MAP4K5, LATS1, LATS2, LCK, L CK2/ICK, LKB1, LIMK1, LOK/STK10, LRRK2, LYN, LYNB, MAPKAPK2, MAPKAPK3, MAPKAPK5/PRAK, MARK1, MARK2/PAR-1Ba, MARK3, MARK4, MEK1, MEK2, MEKK1, MEKK2, MEKK3, MELK, MINK/MINK1, MKK4, MKK6, MLCK/MYLK, MLCK2/MYLK2, MLK1/MAP3K9, MLK2/MAP3K10, MLK3/MAP3K11, MN K1, MNK2, MRCKa/, CDC42BPA, MRCKb/, CDC42BPB, MSK1/RPS6KA5, MSK2/RPS6KA4, MSSK1/STK23, MST1/STK4, MST2/STK3, MST3/STK24, MST4, mTOR/FRAP1, MUSK, MYLK3, MYO3b, NEK1, NEK2, NEK3, NEK4, NEK6, NEK7, NEK9, NEK11, NIK/MAP3K14, NLK, OSR1/OXSR1, P38a/MAPK14, P 38b/MAPK11, P38d/MAPK13, P38g/MAPK12, P70S6K/RPS6KB1, p70S6Kb/, RPS6KB2, PAK1, PAK2, PAK3, PAK4, PAK5, PAK6, PASK, PBK/TOPK, PDGFRa, PDGFRb, PDK1/PDPK1, PDK1/PDHK1, PDK2/PDHK2, PDK3/PDHK3, PDK4/PDHK4, PHKg1, PHKg2, PI3Ka, (p110a/p85a), PI3Kb, (p110b/ p85a), PI3Kd, (p110d/p85a), PI3Kg(p120g), PIM1, PIM2, PIM3, PKA, PKAcb, PKAcg, PKCa, PKCb1, PKCb2, PKCd, PKCepsilon, PKCeta, PKCg, PKCiota, PKCmu/PRKD1, PKCnu/PRKD3, PKCtheta, PKCzeta, PKD2/PRKD2, PKG1a, PKG1b, PKG2/PRKG2, PKN1/PRK1, PKN2/PRK2, PKN3/P RK3, PLK1, PLK2, PLK3, PLK4/SAK, PRKX, PYK2, RAF1, RET, RIPK2, RIPK3, RIPK5, ROCK1, ROCK2, RON/MST1R, ROS/ROS1, RSK1, RSK2, RSK3, RSK4, SGK1, SGK2, SGK3/SGKL, SIK1, SIK2, SLK/STK2, SNARK/NUAK2, SRMS, SSTK/TSSK6, STK16, STK22D/TSSK1, STK25/YSK1, STK32b/YANK 2, STK32c/YANK3, STK33, STK38/NDR1, STK38L/NDR2, STK39/STLK3, SRPK1, SRPK2, SYK, TAK1, TAOK1, TAOK2/TAO1, TAOK3/JIK, TBK1, TEC, TESK1, TGFBR2, TIE2/TEK, TLK1, TLK2, TNIK, TNK1, TRKA, TRKB, TRKC, TRPM7/CHAK1, TSSK2, TSSK3/STK22C, TTBK1, TTBK2, TTK, TXK, TY K1/LTK, TYK2, TYRO3/SKY, ULK1, ULK2, ULK3, VRK1, VRK2, WEE1, WNK1, WNK2, WNK3, YES/YES1, ZAK/MLTK, ZAP70, ZIPK/DAPK3, KINASE, MUTANTS, ABL1(E255K), ABL1(F317I), ABL1(G250E), ABL1(H396P), ABL1(M351T), ABL1(Q252H), ABL1(T315I), ABL1(Y253F), ALK(C1156Y) , ALK(L1196M), ALK(F1174L), ALK(R1275Q), BRAF(V599E), BTK(E41K), CHK2(I157T), c-Kit(A829P), c-KIT(D816H), c-KIT(D816V), c-Kit(D820E), c-Kit(N822K), C-Kit(T670I), c-Kit(V559D), c-Kit(V559D/V654A), c-Kit(V559D/T670I), C-Kit(V560G), c-KIT(V654 A), c-MET(D1228H), C-MET(D1228N), C-MET(F1200I), c-MET(M1250T), C-MET(Y1230A), C-MET(Y1230C), C-MET(Y1230D), C-MET(Y1230H), c-Src(T341M), EGFR(G719C), EGFR(G719S), EGFR(L858R), EGFR(L861Q), EGFR(T790M), EGFR, (L858R, T790M), EGFR(d746-750/T79 0M), EGFR(d746-750), EGFR(d747-749/A750P), EGFR(d747-752/P753S), EGFR(d752-759), FGFR1(V561M), FGFR2(N549H), FGFR3(G697C), FGFR3(K650E), FGFR3(K650M), FGFR4(N535K), FGFR4(V550E), FGFR4(V550L), FLT3(D835Y), FLT3(ITD), JAK2(V617F), LRRK2(G201 9S), LRRK2(I2020T), LRRK2(R1441C), p38a(T106M), PDGFRa(D842V), PDGFRa(T674I), PDGFRa(V561D), RET(E762Q), RET(G691S), RET(M918T), RET(R749T), RET(R813Q), RET(V804L), RET(V804M), RET(Y791F), TIF2(R849W), TIF2(Y897S), and TIF2(Y1108F).
本発明の別の態様において、対象化合物は、非キナーゼ生物学的標的、経路、又はプロセスをモジュレートする1種以上の標的抗癌剤と組み合わせて投与することができる。そのような標的経路、又はプロセスとしては、限定はされないが、ヒートショックタンパク質(例えば、HSP90)、ポリ-ADP(アデノシン二リン酸)-リボースポリメラーゼ(PARP)、低酸素誘導因子(HIF)、プロテアソーム、Wnt/Hedgehog/Notchシグナル伝達タンパク質、TNF-アルファ、マトリックスメタロプロテアーゼ、ファルネシルトランスフェラーゼ、アポトーシス経路(例えば、Bcl-xL、Bcl-2、Bcl-w)、ヒストンデアセチラーゼ(HDAC)、ヒストンアセチルトランスフェラーゼ(HAT)、及びメチルトランスフェラーゼ(例えば、ヒストンリシンメチルトランスフェラーゼ、ヒストンアルギニンメチルトランスフェラーゼ、DNAメチルトランスフェラーゼなど)、及び他の免疫療法(例えば、抗PD1、抗PDL1、抗CTLA4、CAR-T、IDO、A2Aアンタゴニストなど)が挙げられる。 In another aspect of the invention, the subject compounds can be administered in combination with one or more targeted anti-cancer agents that modulate non-kinase biological targets, pathways, or processes, including, but not limited to, heat shock proteins (e.g., HSP90), poly-ADP (adenosine diphosphate)-ribose polymerase (PARP), hypoxia inducible factor (HIF), proteasome, Wnt/Hedgehog/Notch signaling proteins, TNF-alpha, matrix metalloproteases, farnesyltransferases, apoptotic pathways (e.g., Bcl-xL, Bcl-2, Bcl-w), histone deacetylases (HDACs), histone acetyltransferases (HATs), and methyltransferases (e.g., histone lysine methyltransferase, histone arginine methyltransferase, DNA methyltransferase, etc.), and other immunotherapies (e.g., anti-PD1, anti-PDL1, anti-CTLA4, CAR-T, IDO, A2A antagonists, etc.).
本発明の別の態様において、本発明の化合物は、他の抗癌剤の1種以上と組み合わせて投与され、これらの抗癌剤としては、限定はされないが、遺伝子療法、RNAi癌療法、化学的保護剤(例えば、アミホスチン、メスナ、及びデクスラゾキサン)、抗体コンジュゲート(例えばブレンツキシマブベドチン、イブリツモマブチウキセタン)、癌免疫療法、例えば、インターロイキン-2、癌ワクチン(例えば、シプリューセル-T)又はモノクローナル抗体(例えば、ベバシズマブ、アレムツズマブ、リツキシマブ、トラスツズマブなど)が挙げられる。 In another aspect of the invention, the compounds of the invention are administered in combination with one or more other anti-cancer agents, including, but not limited to, gene therapy, RNAi cancer therapy, chemoprotectants (e.g., amifostine, mesna, and dexrazoxane), antibody conjugates (e.g., brentuximab vedotin, ibritumomab tiuxetan), cancer immunotherapy, such as interleukin-2, cancer vaccines (e.g., sipuleucel-T), or monoclonal antibodies (e.g., bevacizumab, alemtuzumab, rituximab, trastuzumab, etc.).
本発明の別の態様において、対象化合物は、放射線療法又は手術と組み合わせて投与される。放射線は一般的に内部で(癌部位付近の放射性物質のインプランテーション)又はフォトン(X線又はガンマ線)若しくは粒子放射線を採用する機器で外部から送達される。併用療法が放射線治療をさらに含む場合、放射線治療は、治療剤と放射線治療の組合せの同時作用から有益な効果が達成される限り、任意の適切な時間に行うことができる。例えば、適切な場合には、放射線治療が治療剤の投与から、おそらく数日間又は数週間もの間一時的に中断されても有益な効果は依然として達成される。 In another aspect of the invention, the subject compounds are administered in combination with radiation therapy or surgery. Radiation is generally delivered internally (implantation of a radioactive material near the cancer site) or externally with a device employing photon (X-rays or gamma rays) or particle radiation. When the combination therapy further includes radiation therapy, the radiation therapy can be administered at any suitable time, so long as a beneficial effect is achieved from the simultaneous action of the combination of the therapeutic agent and the radiation therapy. For example, in appropriate cases, a beneficial effect is still achieved when the radiation therapy is temporarily interrupted from administration of the therapeutic agent, perhaps for days or even weeks.
特定の実施形態において、本発明の化合物は、放射線療法、手術、又は抗癌剤の1種以上と組み合わせて投与され、これらとしては、限定はされないが、DNA損傷剤、代謝拮抗剤、トポイソメラーゼ阻害剤、抗微小管剤、キナーゼ阻害剤、エピジェネティック剤、HSP90阻害剤、PARP阻害剤、及び抗体標的化VEGF、HER2、EGFR、CD50、CD20、CD30、CD33などが挙げられる。 In certain embodiments, the compounds of the invention are administered in combination with radiation therapy, surgery, or one or more anti-cancer agents, including, but not limited to, DNA damaging agents, antimetabolites, topoisomerase inhibitors, anti-microtubule agents, kinase inhibitors, epigenetic agents, HSP90 inhibitors, PARP inhibitors, and antibodies targeting VEGF, HER2, EGFR, CD50, CD20, CD30, CD33, and the like.
特定の実施形態において、本発明の化合物は、アバレリクス、アビラテロン酢酸エステル、アルデスロイキン、アレムツズマブ、アルトレタミン、アナストロゾール、アスパラギナーゼ、ベンダムスチン、ベバシズマブ、ベキサロテン、ビカルタミド、ブレオマイシン、ボルテゾミブ、ブレンツキシマブベドチン、ブスルファン、カペシタビン、カルボプラチン、カルムスチン、セツキシマブ、クロラムブシル、シスプラチン、クラドリビン、クロファラビン、クロミフェン、クリゾチニブ、シクロホスファミド、ダサチニブ、ダウノルビシンリポソーム、デシタビン、デガレリクス、デニロイキンジフチトクス、デニロイキンジフチトクス、デノスマブ、ドセタキセル、ドキソルビシン、ドキソルビシンリポソーム、エピルビシン、エリブリンメシル酸塩、エルロチニブ、エストラムスチン、リン酸エトポシド、エベロリムス、エキセメスタン、フルダラビン、フルオロウラシル、フォテムスチン、フルベストラント、ゲフィチニブ、ゲムシタビン、ゲムツズマブオゾガマイシン、ゴセレリン酢酸塩、酢酸ヒストレリン、ヒドロキシウレア、イブリツモマブチウキセタン、イダルビシン、イホスファミド、イマチニブメシル酸塩、インターフェロンアルファ2a、イピリムマブ、イクサベピロン、ラパチニブトシル酸塩、レナリドミド、レトロゾール、ロイコボリン、ロイプロリド酢酸塩、レバミソール、ロムスチン、メクロレタミン、メルファラン、メトトレキセート、マイトマイシンC、ミトキサントロン、ネララビン、ニロチニブ、オキサリプラチン、パクリタキセル、パクリタキセルタンパク質結合粒子、パミドロネート、パニツムマブ、ペグアスパルガーゼ、ペグインターフェロンアルファ-2b、ペメトレキセド二ナトリウム、ペントスタチン、ラロキシフェン、リツキシマブ、ソラフェニブ、ストレプトゾシン、スニチニブマレエート、タモキシフェン、テムシロリムス、テニポシド、サリドマイド、トレミフェン、トシツモマブ、トラスツズマブ、トレチノイン、ウラムスチン、バンデタニブ、ベムラフェニブ、ビノレルビン、ゾレドロネート、ペムブロリズマブ、ニボルマブ、アテゾリズマブ、デュルバルマブ、アベルマブ、チサゲンレクルユーセル、アキシカブタゲンシロロイセル、放射線療法、又は手術の1種以上と組み合わせて投与される。 In certain embodiments, the compounds of the present invention are selected from the group consisting of abarelix, abiraterone acetate, aldesleukin, alemtuzumab, altretamine, anastrozole, asparaginase, bendamustine, bevacizumab, bexarotene, bicalutamide, bleomycin, bortezomib, brentuximab vedotin, busulfan, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, clomiphene, crizotinib, cyclophosphamide, dasatinib, and daunorubicin. Liposomal, decitabine, degarelix, denileukin diftitox, denileukin diftitox, denosumab, docetaxel, doxorubicin, doxorubicin liposomal, epirubicin, eribulin mesylate, erlotinib, estramustine, etoposide phosphate, everolimus, exemestane, fludarabine, fluorouracil, fotemustine, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate, hydroxyurea, ibritumomab tiuxetan, idarubicin , ifosfamide, imatinib mesylate, interferon alfa-2a, ipilimumab, ixabepilone, lapatinib tosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lomustine, mechlorethamine, melphalan, methotrexate, mitomycin C, mitoxantrone, nelarabine, nilotinib, oxaliplatin, paclitaxel, paclitaxel protein-bound particles, pamidronate, panitumumab, pegaspargase, peginterferon alfa-2b, pemetrexed It is administered in combination with one or more of the following: disodium, pentostatin, raloxifene, rituximab, sorafenib, streptozocin, sunitinib maleate, tamoxifen, temsirolimus, teniposide, thalidomide, toremifene, tositumomab, trastuzumab, tretinoin, uramustine, vandetanib, vemurafenib, vinorelbine, zoledronate, pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, tisagenlecleucel, axicabtageneciloleucel, radiation therapy, or surgery.
本発明は、新生物疾患又は自己免疫疾患を予防又は治療する方法をさらに提供する。一実施形態において、本発明は、対象に治療有効量の本発明の化合物を投与するステップを含む、治療を必要とする対象において新生物疾患又は自己免疫疾患を治療する方法に関する。一実施形態において、本発明は、新生物疾患又は自己免疫疾患を停止させる又は減少させるための薬剤の製造における、本発明の化合物の使用をさらに提供する。 The present invention further provides a method for preventing or treating a neoplastic or autoimmune disease. In one embodiment, the present invention relates to a method for treating a neoplastic or autoimmune disease in a subject in need of treatment, comprising administering to the subject a therapeutically effective amount of a compound of the present invention. In one embodiment, the present invention further provides the use of a compound of the present invention in the manufacture of a medicament for arresting or reducing a neoplastic or autoimmune disease.
特定の実施形態において、新生物疾患は、肺癌、頭頸部癌、中枢神経系癌、前立腺癌、精巣癌、結腸直腸癌、膵臓癌、肝臓癌、胃癌、胆管癌、食道癌、消化管間質腫瘍、乳癌、子宮頸癌、卵巣癌、子宮癌、白血病、リンパ腫、多発性骨髄腫、黒色腫、基底細胞癌、扁平上皮癌、膀胱癌、腎臓癌、肉腫、中皮腫、胸腺腫、骨髄異形成症候群、又は骨髄増殖性疾患である。 In certain embodiments, the neoplastic disease is lung cancer, head and neck cancer, central nervous system cancer, prostate cancer, testicular cancer, colorectal cancer, pancreatic cancer, liver cancer, gastric cancer, bile duct cancer, esophageal cancer, gastrointestinal stromal tumor, breast cancer, cervical cancer, ovarian cancer, uterine cancer, leukemia, lymphoma, multiple myeloma, melanoma, basal cell carcinoma, squamous cell carcinoma, bladder cancer, kidney cancer, sarcoma, mesothelioma, thymoma, myelodysplastic syndrome, or myeloproliferative disease.
本発明による化合物及び組成物の使用により影響を受け得る自己免疫疾患としては、限定はされないが、アレルギー、アルツハイマー病、急性散在性脳脊髄炎、アジソン病、強直性脊椎炎、抗リン脂質抗体症候群、喘息、アテローム性動脈硬化症、自己免疫性溶血性貧血、自己免疫性の溶血性及び血小板減少症の状態、自己免疫性肝炎、自己免疫性内耳疾患、水疱性類天疱瘡、セリアック病、シャーガス病、慢性閉塞性肺疾患、慢性特発性血小板減少性紫斑病(ITP)、チャーグストラウス症候群、クローン病、皮膚筋炎、真性糖尿病1型、子宮内膜症、グッドパスチャー症候群(及びそれに伴う糸球体腎炎及び肺出血)、グレーヴス病、ギランバレー症候群、橋本病、化膿性汗腺炎、特発性血小板減少性紫斑病、間質性膀胱炎、過敏性腸症候群、エリテマトーデス、モルフェア、多発性硬化症、重症筋無力症、ナルコレプシー、神経性筋緊張病、パーキンソン病、尋常性天疱瘡、悪性貧血、多発性筋炎、原発性胆汁性肝硬変、乾癬、乾癬性関節炎、関節リウマチ、統合失調症、敗血症性ショック、強皮症、シェーグレン症候群、全身性エリテマトーデス(及びこれに伴う糸球体腎炎)、側頭動脈炎、組織移植片拒絶及び移植器官の超急性拒絶、血管炎(ANCA関連及び他の脈管炎)、尋常性白斑、及びウェゲナー肉芽腫症が挙げられる。 Autoimmune diseases that may be affected by the use of the compounds and compositions according to the present invention include, but are not limited to, allergies, Alzheimer's disease, acute disseminated encephalomyelitis, Addison's disease, ankylosing spondylitis, antiphospholipid syndrome, asthma, atherosclerosis, autoimmune hemolytic anemia, autoimmune hemolytic and thrombocytopenic conditions, autoimmune hepatitis, autoimmune inner ear disease, bullous pemphigoid, celiac disease, Chagas disease, chronic obstructive pulmonary disease, chronic idiopathic thrombocytopenic purpura (ITP), Churg-Strauss syndrome, Crohn's disease, dermatomyositis, diabetes mellitus type 1, endometriosis, Goodpasture's syndrome (and associated glomerulonephritis and pulmonary hemorrhage) , Graves' disease, Guillain-Barre syndrome, Hashimoto's disease, hidradenitis suppurativa, idiopathic thrombocytopenic purpura, interstitial cystitis, irritable bowel syndrome, lupus erythematosus, morphea, multiple sclerosis, myasthenia gravis, narcolepsy, neuromyotonia, Parkinson's disease, pemphigus vulgaris, pernicious anemia, polymyositis, primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, schizophrenia, septic shock, scleroderma, Sjogren's syndrome, systemic lupus erythematosus (and associated glomerulonephritis), temporal arteritis, tissue graft rejection and hyperacute rejection of transplanted organs, vasculitis (ANCA-associated and other vasculitides), vitiligo vulgaris, and Wegener's granulomatosis.
本発明は、本明細書に示され記載される特定の実施形態に限定はされないが、特許請求の範囲によって定義される本発明の精神及び範囲から逸脱することなく、様々な変更及び修正を行うことができることを理解するべきである。 It should be understood that the present invention is not limited to the specific embodiments shown and described herein, but that various changes and modifications can be made without departing from the spirit and scope of the present invention as defined by the claims.
本発明による化合物は、様々なスキームにしたがって合成されてもよい。必要な出発物質は、有機化学の標準的手順により得ることができる。本発明の化合物及び方法は、単に例証として意図しており本発明の範囲を限定するものではない、以下の代表的な合成スキーム及び実施例に関連して、さらに良く理解される。開示される実施形態への様々な変更及び修正は当業者にとって明らかとなり、限定はされないが、本発明の化学構造、置換基、誘導体、及び/又は方法に関するものを含めた、そのような変更及び修正は、本発明の精神及び添付の特許請求の範囲から逸脱することなく行うことができる。 The compounds according to the invention may be synthesized according to various schemes. The necessary starting materials may be obtained by standard procedures of organic chemistry. The compounds and methods of the invention will be better understood in connection with the following representative synthetic schemes and examples, which are intended merely as illustrations and are not intended to limit the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art, and such changes and modifications, including but not limited to those relating to the chemical structures, substituents, derivatives, and/or methods of the invention, can be made without departing from the spirit of the invention and the scope of the appended claims.
中間体 Intermediate
スキーム1では、適切なケトン出発物質1-1をトリブロモホスフィンと反応させてアルデヒド中間体1-2を形成することができ、これをBoc保護したピペラジンとカップリングさせて、中間体1-3を形成することができる。その後、Suzuki反応を介して、1-3を適切なフェニルボロン酸とカップリングさせて中間体1-4を形成し、続いて脱Bocプロセスを行って主要中間体1-5を得る。 In Scheme 1, the appropriate ketone starting material 1-1 can be reacted with tribromophosphine to form the aldehyde intermediate 1-2, which can be coupled with a Boc-protected piperazine to form intermediate 1-3. 1-3 can then be coupled via a Suzuki reaction with an appropriate phenylboronic acid to form intermediate 1-4, followed by a de-Boc process to give the key intermediate 1-5.
中間体 Intermediate
スキーム2では、出発物質2-1を適切なアルコール又はアミンを反応させて、2-2を得る。 In Scheme 2, starting material 2-1 is reacted with an appropriate alcohol or amine to give 2-2.
スキーム4では、市販の出発物質3-6の遊離NHの保護により3-7が得られ、これを塩基の存在下で3,3-ジエトキシプロパン-1-オールと反応させて、アルコキシド中間体4-2を形成することができる。これに続くNH2BocとのBuckwaldカップリングにより、中間体4-3が得られ、タンデム反応:Boc基の脱保護、7員環式イミンの形成、及び還元においてこれを三環系中間体4-4へと環化することができる。 In Scheme 4, protection of the free NH of commercially available starting material 3-6 gives 3-7, which can be reacted with 3,3-diethoxypropan-1-ol in the presence of base to form the alkoxide intermediate 4-2. Subsequent Buckwald coupling with NH2Boc gives intermediate 4-3, which can be cyclized to the tricyclic intermediate 4-4 in a tandem reaction: deprotection of the Boc group, formation of a seven-membered cyclic imine, and reduction.
方法A Method A
スキーム4-2では、中間体3-1-2(スキーム3において3-1-1から合成)の置換反応によりアルコキシド中間体4-2-1が得られる。これに続くNH2BocとのBuchwald又はUllmannカップリングにより中間体4-2-2が得られ、ワンポットタンデム反応:Boc基の脱保護、7員環式イミンの形成、及びイミンの還元において三環系中間体4-2-3へと環化することができる。 In Scheme 4-2, substitution reaction of intermediate 3-1-2 (synthesized from 3-1-1 in Scheme 3) gives alkoxide intermediate 4-2-1. Subsequent Buchwald or Ullmann coupling with NH2Boc gives intermediate 4-2-2, which can be cyclized to tricyclic intermediate 4-2-3 in a one-pot tandem reaction: deprotection of the Boc group, formation of a seven-membered cyclic imine, and reduction of the imine.
方法B Method B
スキーム4-3では、3-1-2をアルコキシド中間体4-3-1に変換する。これに続くBuchwald又はUllmann反応閉環により中間体4-3-2が得られ、これに続いてTs基の脱保護により中間体4-3-3を得る。 In Scheme 4-3, 3-1-2 is converted to the alkoxide intermediate 4-3-1. Subsequent Buchwald or Ullmann ring closure affords intermediate 4-3-2, which is then followed by deprotection of the Ts group to afford intermediate 4-3-3.
方法C Method C
スキーム4-4では、3-1-2をアルコキシド中間体4-4-1に変換する。これに続くNH2-TsとのBuchwaldカップリング又はUllmann反応により、中間体4-4-2を得る。これに続いて4-4-2のMitsunobu閉環により中間体4-4-3を得る。最後に、Ts基の脱保護により中間体4-4-4を得る。 In scheme 4-4, 3-1-2 is converted to the alkoxide intermediate 4-4-1. Subsequent Buchwald coupling or Ullmann reaction with NH2 -Ts gives intermediate 4-4-2. Subsequent Mitsunobu ring closure of 4-4-2 gives intermediate 4-4-3. Finally, deprotection of the Ts group gives intermediate 4-4-4.
方法A Method A
スキーム4-5では、中間体3-1-2(スキーム3の3-1-1から合成)の置換反応により中間体4-5-1が得られる。これに続くNH2BocとのBuchwald又はUllmannカップリングにより中間体4-5-2が得られ、ワンポットタンデム反応:Boc基の脱保護、7員環式イミンの形成、及び還元においてこれを三環系中間体4-5-3に環化することができる。 In Scheme 4-5, substitution reaction of intermediate 3-1-2 (synthesized from 3-1-1 in Scheme 3) gives intermediate 4-5-1. Subsequent Buchwald or Ullmann coupling with NH2Boc gives intermediate 4-5-2, which can be cyclized to tricyclic intermediate 4-5-3 in a one-pot tandem reaction: deprotection of the Boc group, formation of a seven-membered cyclic imine, and reduction.
方法B Method B
スキーム4-6では、3-1-2を中間体4-6-1に変換する。これに続くBuchwald又はUllmann反応の閉環により中間体4-6-2が得られ、続いてTs基の脱保護により中間体4-6-3を得る。 In Scheme 4-6, 3-1-2 is converted to intermediate 4-6-1. Subsequent ring closure in a Buchwald or Ullmann reaction gives intermediate 4-6-2, followed by deprotection of the Ts group to give intermediate 4-6-3.
方法C Method C
スキーム4-7では、求核性芳香族置換を介して3-1-2を中間体4-7-1に変換する。エステル4-7-1(R=Me、Et)の還元により中間体4-7-2を形成する。これに続くNH2-TsとのBuchwald又はUllmannカップリングにより、中間体4-7-3が得られ、Mitsunobu閉環を施すことにより4-7-4が形成され、続いてTs基の脱保護により中間体4-7-5を得る。 In Scheme 4-7, 3-1-2 is converted to intermediate 4-7-1 via nucleophilic aromatic substitution. Reduction of ester 4-7-1 (R = Me, Et) forms intermediate 4-7-2. Subsequent Buchwald or Ullmann coupling with NH2 -Ts gives intermediate 4-7-3, which undergoes Mitsunobu ring closure to form 4-7-4, followed by deprotection of the Ts group to give intermediate 4-7-5.
(式中、Z2、R9、及びkは上記の発明の概要の章で記載されるのと同じである)を合成するための典型的な方法を以下のスキーム4-8に記載する。 Exemplary methods for the synthesis of: (wherein Z 2 , R 9 , and k are as described in the Summary of the Invention section above) are described below in Schemes 4-8.
スキーム4-8では、4-8-1(スキーム4-5、4-6、4-7から合成)のチオエーテルN-酸化をm-CPBAを反応させて中間体4-8-2を形成する。 In Scheme 4-8, the thioether N-oxide of 4-8-1 (synthesized from Schemes 4-5, 4-6, and 4-7) is reacted with m-CPBA to form intermediate 4-8-2.
中間体 Intermediate
他の中間体 Other intermediates
式(D)化合物(式中、Z2はOである)を合成するための典型的な方法をスキームIIに記載する: An exemplary method for synthesizing compounds of formula (D) where Z2 is O is described in Scheme II:
スキームIIでは、中間体1-5に、選択されたp-フルオロ-2-ブロモ-ベンゾエートとの求核性芳香族置換を施してII-2を得る。適切なアミン中間体とのII-2のBuckwaldカップリングによりII-3が得られる。II-3をTFAで順次に脱保護してSEM基及びNaOHを除去して、エステル基を除去し、遊離カルボン酸中間体II-5を得る。II-5の2-2とのカップリングにより式(D)の最終生成物を得る。 In Scheme II, intermediate 1-5 undergoes nucleophilic aromatic substitution with a selected p-fluoro-2-bromo-benzoate to give II-2. Buckwald coupling of II-2 with an appropriate amine intermediate gives II-3. II-3 is sequentially deprotected with TFA to remove the SEM group and NaOH to remove the ester group to give the free carboxylic acid intermediate II-5. Coupling of II-5 with 2-2 gives the final product of formula (D).
異なるZを有する式(D)の化合物は、適切な出発物質及び中間体を使用することによって、一般スキームIIと同様の方法により調製することができる。 Compounds of formula (D) having different Z can be prepared in a similar manner to general scheme II by using appropriate starting materials and intermediates.
式(C)、(B)、及び(A)の化合物は、適切な出発物質及び中間体を使用することによって、一般スキームIIと同様の方法により調製することができる。 Compounds of formula (C), (B), and (A) can be prepared by methods similar to those of general scheme II by using appropriate starting materials and intermediates.
本発明の化合物及び方法は、単に例証として意図しており本発明の範囲を限定するものではない、以下の実施例に関連して、さらに良く理解される。開示される実施形態への様々な変更及び修正は当業者にとって明らかとなり、限定はされないが、本発明の化学構造、置換基、誘導体、製剤、及び/又は方法に関するものを含めた、そのような変更及び修正は、本発明の精神及び添付の特許請求の範囲から逸脱することなく行うことができる。 The compounds and methods of the present invention will be better understood in connection with the following examples, which are intended to be merely illustrative and not limiting of the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art, and such changes and modifications, including but not limited to those relating to the chemical structures, substituents, derivatives, formulations, and/or methods of the invention, can be made without departing from the spirit of the invention and the scope of the appended claims.
NMRデータが示される場合、1HスペクトルはXL400(400 MHz)において得られたものであり、挿入句的に示されるプロトンの数、多重度、及びヘルツでの結合定数と共に、Me4Siから低磁場側のppmとして報告される。HPLCデータが示される場合、Agilent 1100システムを使用して分析を行った。LC/MSデータが示される場合、Applied Biosystems API-100質量分析計及びShimadzu SCL-10A LCカラムを使用して分析を行った。 Where NMR data is given, 1 H spectra were obtained on an XL400 (400 MHz) and are reported as ppm downfield from Me 4 Si, with the number of protons, multiplicities, and coupling constants in Hertz given parenthetically. Where HPLC data is given, analyses were performed using an Agilent 1100 system. Where LC/MS data is given, analyses were performed using an Applied Biosystems API-100 mass spectrometer and a Shimadzu SCL-10A LC column.
[実施例1-1]
1-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジンの調製
2-ブロモ-4,4-ジメチルシクロヘキサ-1-エンカルボアルデヒド2の合成:無水クロロホルム(57ml)及び無水N,N-ジメチルホルムアミド(9mL)の溶液を約3℃(内部温度)に窒素下で冷却してから、三臭化リン(10mL、0.1モル)を、反応が約3℃で維持されるような速度で滴下により導入した。添加完了後、反応物をゆっくりと約10℃に温め、次いで温度を70℃に上昇させ、この温度で30分間維持した。反応物を室温に冷却し、3,3-ジメチルシクロヘキサノン1(5g、0.04モル)を20分間にわたりゆっくりと加えた。添加完了後、反応物を70℃に温め、1.5時間撹拌した。次いで混合物を0℃に冷却し、4M酢酸ナトリウムの溶液(53ml)をゆっくりと加えた。5M NaOH溶液を使用して、得られる溶液のpHを約7に調整し、次いで混合物をヘプタン(100mL×3)で抽出した。合わせた有機画分を乾燥させ(Na2SO4)、ろ過し、減圧下で濃縮して、2-ブロモ-4,4-ジメチルシクロヘキサ-1-エンカルボアルデヒド2(4g、49%)が黄色油状物として得られた。
[Example 1-1]
Preparation of 1-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine
Synthesis of 2-bromo-4,4-dimethylcyclohex-1-enecarbaldehyde 2: A solution of anhydrous chloroform (57 ml) and anhydrous N,N-dimethylformamide (9 mL) was cooled to about 3° C. (internal temperature) under nitrogen, then phosphorus tribromide (10 mL, 0.1 mol) was introduced dropwise at such a rate that the reaction was maintained at about 3° C. After the addition was complete, the reaction was slowly warmed to about 10° C., then the temperature was increased to 70° C. and maintained at this temperature for 30 minutes. The reaction was cooled to room temperature and 3,3-dimethylcyclohexanone 1 (5 g, 0.04 mol) was added slowly over 20 minutes. After the addition was complete, the reaction was warmed to 70° C. and stirred for 1.5 hours. The mixture was then cooled to 0° C. and a solution of 4 M sodium acetate (53 ml) was added slowly. The pH of the resulting solution was adjusted to about 7 using 5 M NaOH solution, and then the mixture was extracted with heptane ( 100 mL x 3). The combined organic fractions were dried ( Na2SO4 ), filtered, and concentrated under reduced pressure to give 2-bromo-4,4-dimethylcyclohex-1-enecarbaldehyde 2 (4 g, 49%) as a yellow oil.
2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エンカルボアルデヒド3の合成:2-ブロモ-4,4-ジメチルシクロヘキサ-1-エンカルボアルデヒド2(5g、0.023モル)及び4-クロロフェニルボロン酸(3.6g、0.023モル)の1,4-ジオキサン(50mL)中の脱気した溶液へ、室温で2M Na2CO3(20.4ml)溶液を加えた。混合物に窒素を2分間吹き込み、次いでPdCl2(dppf)(0.5g)を加えた。反応フラスコを120℃に加熱し、この温度で3時間維持した。この後、懸濁液を室温に冷却し、セライトを通してろ過した。回収した固体を追加のジクロロメタンで洗浄し、合わせたろ液及び洗浄液を減圧下で濃縮した。PE:EA=20:1を使用して、シリカによるカラムクロマトグラフィーによる精製により、2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エンカルボアルデヒド3(3g、53%)が白色固体として得られた。MS: 249[M+H]+ Synthesis of 2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enecarbaldehyde 3: To a degassed solution of 2-bromo-4,4-dimethylcyclohex-1-enecarbaldehyde 2 (5 g, 0.023 mol) and 4-chlorophenylboronic acid (3.6 g, 0.023 mol) in 1,4-dioxane (50 mL) was added a 2M Na2CO3 (20.4 ml) solution at room temperature. The mixture was sparged with nitrogen for 2 minutes and then PdCl2 (dppf) (0.5 g) was added. The reaction flask was heated to 120°C and maintained at this temperature for 3 hours. After this time, the suspension was cooled to room temperature and filtered through Celite. The collected solid was washed with additional dichloromethane and the combined filtrate and washings were concentrated under reduced pressure. Purification by column chromatography on silica using PE:EA=20:1 gave 2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enecarbaldehyde 3 (3 g, 53%) as a white solid. MS: 249[M+H] +
(2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エニル)メタノール4の合成:2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エンカルボアルデヒド3(20g、80.6mmol)のMeOH(100mL)中の溶液を0℃に冷却し、NaBH4(3.1g、80.6mmol)を、反応が0~5℃で維持されるような速度で反応物に少しずつ加えた。添加後、混合物を0℃で1時間撹拌した。水を混合物にゆっくりと加え、EA(200mL×3)で抽出し、有機層をブラインで洗浄し、Na2SO4で乾燥させ、ろ過し、減圧下で濃縮して、(2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エニル)メタノール4(15g、75%)が白色固体として得られた。MS: 233[M+H-H2O]+ Synthesis of (2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methanol 4: A solution of 2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enecarbaldehyde 3 (20 g, 80.6 mmol) in MeOH (100 mL) was cooled to 0° C. and NaBH 4 (3.1 g, 80.6 mmol) was added to the reaction in portions at such a rate that the reaction was maintained at 0-5° C. After the addition, the mixture was stirred at 0° C. for 1 h. Water was slowly added to the mixture and extracted with EA (200 mL×3), the organic layer was washed with brine, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give (2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methanol 4 (15 g, 75%) as a white solid. MS: 233[M+HH 2 O] +
1-(2-(ブロモメチル)-5,5-ジメチルシクロヘキサ-1-エニル)-4-クロロベンゼン5の合成:(2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エニル)メタノール4(15g、0.060モル)のEt2O(300ml)中の溶液を0℃に冷却してから、三臭化リン(7.5mL)を混合物に滴下して加え、添加後、混合物を1時間0℃で90分間撹拌した。反応混合物をH2Oに加えてから、EAで抽出した。有機層をNaHCO3飽和溶液及びブラインで洗浄し、Na2SO4で乾燥させ、ろ過し、減圧下で濃縮して、1-(2-(ブロモメチル)-5,5-ジメチルシクロヘキサ-1-エニル)-4-クロロベンゼン5(18g、96%)が無色油状物として得られた。 Synthesis of 1-(2-(bromomethyl)-5,5-dimethylcyclohex-1-enyl)-4-chlorobenzene 5: A solution of (2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methanol 4 (15 g, 0.060 mol) in Et2O (300 ml) was cooled to 0°C, then phosphorus tribromide (7.5 mL) was added dropwise to the mixture, after addition the mixture was stirred at 0°C for 90 min for 1 h. The reaction mixture was added to H2O , then extracted with EA. The organic layer was washed with NaHCO3 saturated solution and brine , dried over Na2SO4 , filtered and concentrated under reduced pressure to give 1-(2-(bromomethyl)-5,5-dimethylcyclohex-1-enyl)-4-chlorobenzene 5 (18 g, 96%) as a colorless oil.
tert-ブチル4-((2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エニル)メチル)ピペラジン-1-カルボキシレートの合成 - 1-ブロモ-2-(ブロモメチル)-5,5-ジメチルシクロヘキサ-1-エン5(21g、0.067モル)及びtert-ブチルピペラジン-1-カルボキシレート(12.4g、0.067モル)のジクロロメタン(200ml)中の溶液へ、TEA(12.2g、0.12モル)を室温で加えた。反応物を2時間撹拌した。反応混合物を減圧下で濃縮して粗生成物を得た。PE:EA=20:1を使用して、シリカによるカラムクロマトグラフィーによる精製により、tert-ブチル4-((2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エニル)メチル)ピペラジン-1-カルボキシレート6(21g、75%)が得られた。 Synthesis of tert-butyl 4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine-1-carboxylate - To a solution of 1-bromo-2-(bromomethyl)-5,5-dimethylcyclohex-1-ene 5 (21 g, 0.067 mol) and tert-butyl piperazine-1-carboxylate (12.4 g, 0.067 mol) in dichloromethane (200 ml) was added TEA (12.2 g, 0.12 mol) at room temperature. The reaction was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure to give the crude product. Purification by column chromatography on silica using PE:EA=20:1 gave tert-butyl 4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine-1-carboxylate 6 (21 g, 75%).
1-((2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エニル)メチル)ピペラジン塩化水素の合成:tert-ブチル4-((2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エニル)メチル)ピペラジン-1-カルボキシレート6(30g、0.072モル)のMeOH(20ml)中の溶液へ濃HCl(50mL)を加えた。反応物を24時間撹拌し、次いで減圧下で濃縮した。Na2CO3の飽和溶液を加え、pHを約8~9に調整し、混合物をジクロロメタン(×2)で抽出した。合わせた抽出物をブラインで洗浄し、乾燥させ(Na2SO4)、ろ過し、減圧下で濃縮した。油生成物をMeOH/HCl(g)(3M、500mL)で処理し、1時間撹拌し、次いで減圧下で濃縮して、生成物1-((2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エニル)メチル)ピペラジン塩化水素IM-14-1(23g、83%)が得られた。MS: 319[M+H]+ 1H NMR (400 MHz, DMSO) δ 11.51 (s, 1H), 9.60 (s, 1H), 9.18 (s, 1H), 7.45 (d, J = 8.2 Hz, 2H), 7.15 (d, J = 8.0 Hz, 2H), 3.43 (s, 8H), 2.84 (s, 2H), 2.39 (s, 2H), 2.03 (s, 2H), 1.45 (t, J = 6.0 Hz, 2H), 0.96 (s, 6H). Synthesis of 1-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine hydrochloride: To a solution of tert-butyl 4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine- 1 -carboxylate 6 (30 g, 0.072 mol) in MeOH (20 ml) was added concentrated HCl (50 mL). The reaction was stirred for 24 h and then concentrated under reduced pressure. A saturated solution of Na2CO3 was added to adjust the pH to about 8-9 and the mixture was extracted with dichloromethane ( x2 ). The combined extracts were washed with brine, dried ( Na2SO4 ), filtered and concentrated under reduced pressure. The oil product was treated with MeOH/HCl(g) (3M, 500 mL), stirred for 1 h, and then concentrated under reduced pressure to give the product 1-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine hydrochloride IM-14-1 (23 g, 83%). MS: 319[M+H] + 1H NMR (400 MHz, DMSO) δ 11.51 (s, 1H), 9.60 (s, 1H), 9.18 (s, 1H), 7.45 (d, J = 8.2 Hz, 2H), 7.15 (d, J = 8.0 Hz, 2H), 3.43 (s, 8H), 2.84 (s, 2H), 2.39 (s, 2H), 2.03 (s, 2H), 1.45 (t, J = 6.0 Hz, 2H), 0.96 (s, 6H).
[実施例1-2]
3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)ベンゼンスルホンアミドの調製
機械撹拌装置を備えた500mL三つ口RBフラスコへ、4-クロロ-3-ニトロベンゼンスルホンアミド(23.7g、100mmol)、DIPEA(12.9g、100mmol)、(テトラヒドロ-2H-ピラン-4-イル)メタンアミン(11.5g、100mmol)及びアセトニトリル(200mL)を充填した。反応混合物を内部温度80℃に調整し、12時間以上撹拌した。生成物溶液を40℃に冷却し、析出が観察されるまで1時間以上撹拌した。生成物スラリーを20℃にさらに冷却した。水(80mL)を1時間以上にわたりゆっくりと充填し、混合物を10℃に冷却し、2時間以上撹拌してから、ろ過によって回収した。湿ったケーキをアセトニトリル:水の1:1ミックス(40mL)で洗浄した。湿ったケーキを40℃で1時間以上水(80mL)ですすいでから、ろ過によって回収した。湿ったケーキを水(20mL)ですすぎ、真空下75℃で乾燥させて、3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)ベンゼンスルホンアミド(24.5g、78%)が橙色固体として得られた。1H NMR (400 MHz, DMSO) δ 8.60 (t, J = 5.9 Hz, 1H), 8.48 (d, J = 2.2 Hz, 1H), 7.84 (dd, J = 9.2, 2.0 Hz, 1H), 7.54 - 7.18 (m, 3H), 3.86 (dd, J = 11.3, 3.2 Hz, 2H), 3.35 (s, 2H), 3.27 (t, J = 10.9 Hz, 2H), 1.92 (ddd, J = 11.2, 7.4, 3.9 Hz, 1H), 1.62 (d, J = 11.4 Hz, 2H), 1.27 (qd, J = 12.3, 4.4 Hz, 2H).
[Example 1-2]
Preparation of 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide. A 500 mL three-necked RB flask equipped with mechanical stirring was charged with 4-chloro-3-nitrobenzenesulfonamide (23.7 g, 100 mmol), DIPEA (12.9 g, 100 mmol), (tetrahydro-2H-pyran-4-yl)methanamine (11.5 g, 100 mmol) and acetonitrile (200 mL). The reaction mixture was adjusted to an internal temperature of 80° C. and stirred for not less than 12 hours. The product solution was cooled to 40° C. and stirred for not less than 1 hour until precipitation was observed. The product slurry was further cooled to 20° C. Water (80 mL) was charged slowly over 1 hour and the mixture was cooled to 10° C. and stirred for not less than 2 hours before being collected by filtration. The wet cake was washed with a 1:1 mix of acetonitrile:water (40 mL). The wet cake was rinsed with water (80 mL) at 40° C. for not less than 1 h and then collected by filtration. The wet cake was rinsed with water (20 mL) and dried under vacuum at 75° C. to give 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (24.5 g, 78%) as an orange solid. 1H NMR (400 MHz, DMSO) δ 8.60 (t, J = 5.9 Hz, 1H), 8.48 (d, J = 2.2 Hz, 1H), 7.84 (dd, J = 9.2, 2.0 Hz, 1H), 7.54 - 7.18 (m, 3H), 3.86 (dd, J = 11.3, 3.2 Hz, 2H), 3.35 (s, 2H), 3.27 (t, J = 10.9 Hz, 2H), 1.92 (ddd, J = 11.2, 7.4, 3.9 Hz, 1H), 1.62 (d, J = 11.4 Hz, 2H), 1.27 (qd, J = 12.3, 4.4 Hz, 2H).
[実施例1-3]
4-[[(4-フルオロオキサン-4-イル)メチル]アミノ]-3-ニトロベンゼン-1-スルホンアミドの調製
50mL丸底フラスコ中へ、(4-フルオロオキサン-4-イル)メタンアミン塩酸塩(500mg、2.95mmol、1.00当量)、4-フルオロ-3-ニトロベンゼン-1-スルホンアミド(650mg、2.95mmol、1.00当量)、テトラヒドロフラン(15mL)、Cs2CO3(2.8g、8.59mmol、3.00当量)を入れた。得られる溶液を油浴中で50℃で14時間撹拌した。反応混合物を室温に冷却した。得られる混合物をろ過し、真空下で濃縮した。残渣を、酢酸エチル/石油エーテル(4:1)を使用してシリカゲルカラムに適用した。これにより650mg(66%)の4-[[(4-フルオロオキサン-4-イル)メチル]アミノ]-3-ニトロベンゼン-1-スルホンアミドが黄色固体として得られた。LCMS (ES, m/z): M+1: 334. H-NMR: (300 MHz, DMSO, ppm): δ 8.58 (t, J=6.3 Hz, 1 H), 8.49 (d, J=2.1 Hz, 1 H), 7.90 - 7.80 (m, 1 H), 7.44 (d, J=9.3 Hz,1 H), 7.34 (s, 2 H), 3.87 - 3.70 (m , 4 H), 3.61 - 3.50 (m, 2 H),1.95 - 1.70 (m, 4 H).
[Examples 1-3]
Preparation of 4-[[(4-fluorooxan-4-yl)methyl]amino]-3-nitrobenzene-1-sulfonamide
Into a 50 mL round bottom flask were placed (4-fluorooxan-4-yl)methanamine hydrochloride (500 mg, 2.95 mmol, 1.00 equiv), 4-fluoro-3-nitrobenzene-1-sulfonamide (650 mg, 2.95 mmol, 1.00 equiv), tetrahydrofuran (15 mL), and Cs2CO3 (2.8 g, 8.59 mmol, 3.00 equiv). The resulting solution was stirred in an oil bath at 50°C for 14 hours. The reaction mixture was cooled to room temperature. The resulting mixture was filtered and concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate/petroleum ether (4:1). This gave 650 mg (66%) of 4-[[(4-fluorooxan-4-yl)methyl]amino]-3-nitrobenzene-1-sulfonamide as a yellow solid. LCMS (ES, m/z): M+1: 334. H-NMR: (300 MHz, DMSO, ppm): δ 8.58 (t, J=6.3 Hz, 1 H), 8.49 (d, J=2.1 Hz, 1 H), 7.90 - 7.80 (m, 1 H), 7.44 (d, J=9.3 Hz,1 H), 7.34 (s, 2 H), 3.87 - 3.70 (m , 4 H), 3.61 - 3.50 (m, 2 H),1.95 - 1.70 (m, 4 H).
[実施例1-4]
7-((2-(トリメチルシリル)エトキシ)メチル)-1,3,4,7-テトラヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピンの調製
5-ブロモ-6-フルオロ-1-[[2-(トリメチルシリル)エトキシ]メチル]-1H-ピロロ[2,3-b]ピリジンの合成:窒素の不活性雰囲気でパージされ維持された250mL三つ口丸底フラスコ中へ、市販の5-ブロモ-6-フルオロ-1H-ピロロ[2,3-b]ピリジン(CAS、1190321-99-3、15 g、69.76 mmol、1.00当量)のN,N-ジメチルホルムアミド(150 mL)中の溶液を入れた。これに続いて、水素化ナトリウム(4.2g、175.00mmol、1.50当量)を0度で少しずつ加えた。0.5時間撹拌後、これに、撹拌しながら0度でSEMCl(14g、84.34mmol、1.20当量)を滴下して加えた。得られる溶液を、撹拌しながら、室温で追加の3時間反応させた。次いで300mLの水を加えることにより反応をクエンチした。得られる溶液を3×200mLの酢酸エチルで抽出し、有機層を合わせた。得られる混合物を3×200mLのブラインで洗浄した。混合物を無水硫酸ナトリウム上で乾燥させ、真空下で濃縮した。残渣を、酢酸エチル/石油エーテル(0:1~1:10)を使用してシリカゲルカラムに適用した。これにより15g(62%)の5-ブロモ-6-フルオロ-1-[[2-(トリメチルシリル)エトキシ]メチル]-1H-ピロロ[2,3-b]ピリジンが黄色油状物として得られた。H-NMR (CDCl3, 300 MHz) δ: 8.19 (d, J=8.7 Hz, 1H), 7.37 (d, J=3.6 Hz, 1H), 6.54 (d, J=3.6 Hz, 1H), 5.64 (s, 2H), 3.58 (t, J=8.1 Hz, 2H), 0.98-0.93 (t, J=8.1 Hz, 2H), 0.00 (s, 9H).
5-ブロモ-6-(3,3-ジエトキシプロポキシ)-1-[[2-(トリメチルシリル)エトキシ]メチル]-1H-ピロロ[2,3-b]ピリジンの合成:窒素の不活性雰囲気でパージされ維持された250mL丸底フラスコ中へ、3,3-ジエトキシプロパン-1-オール(2.6 g、17.38 mmol、1.5当量)、THF(50 mL)を入れた。これに続いてNaH(930 mg、38.75 mmol、3.35当量)を0℃で少しずつ加えた。得られる溶液を25℃で30分間撹拌した。これに、5-ブロモ-6-フルオロ-1-[[2-(トリメチルシリル)エトキシ]メチル]-1H-ピロロ[2,3-b]ピリジン(4 g、11.58 mmol、1当量)のTHF(10 mL)中の溶液を0℃で撹拌しながら滴下して加えた。得られる溶液を25℃で6時間撹拌した。次いで500 mlの水性NH4Clを加えることにより反応をクエンチした。得られる溶液を2×200 mLの酢酸エチルで抽出した。得られる混合物を1×500 mlのブラインで洗浄した。混合物を無水硫酸ナトリウム上で乾燥させ、真空下で濃縮した。残渣を、酢酸エチル/石油エーテル(1:16)を使用してシリカゲルカラムに適用した。これにより4 g(72.92%)の5-ブロモ-6-(3,3-ジエトキシプロポキシ)-1-[[2-(トリメチルシリル)エトキシ]メチル]-1H-ピロロ[2,3-b]ピリジンが黄色油状物として得られた。1H NMR (300 MHz, CDCl3-d, ppm) δ 8.03 (s, 1H), 7.15 (d, J = 3.6 Hz, 1H), 6.39 (d, J = 3.6 Hz, 1H), 5.57 (s, 2H), 4.88 (t, J = 5.8 Hz, 1H), 4.52 (t, J = 6.2 Hz, 2H), 3.75 (dq, J = 9.4, 7.1 Hz, 2H), 3.64 - 3.45 (m, 4H), 2.18 (q, J = 6.1 Hz, 2H), 1.24 (t, J = 7.1 Hz, 6H), 1.01 - 0.79 (m, 2H), -0.04 (s, 9H).BBOFのプローブヘッドを備えたBruker AvanceIII HDでNMRスペクトルの測定を行った。
[Examples 1-4]
Preparation of 7-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine
Synthesis of 5-bromo-6-fluoro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridine: Into a 250 mL three-necked round bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of commercially available 5-bromo-6-fluoro-1H-pyrrolo[2,3-b]pyridine (CAS, 1190321-99-3, 15 g, 69.76 mmol, 1.00 equiv.) in N,N-dimethylformamide (150 mL). This was followed by the addition of sodium hydride (4.2 g, 175.00 mmol, 1.50 equiv.) in portions at 0°C. After stirring for 0.5 h, to this was added SEMCl (14 g, 84.34 mmol, 1.20 equiv.) dropwise at 0°C with stirring. The resulting solution was allowed to react at room temperature with stirring for an additional 3 h. The reaction was then quenched by adding 300 mL of water. The resulting solution was extracted with 3×200 mL of ethyl acetate and the organic layers were combined. The resulting mixture was washed with 3×200 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied to a silica gel column using ethyl acetate/petroleum ether (0:1 to 1:10). This gave 15 g (62%) of 5-bromo-6-fluoro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridine as a yellow oil. H-NMR ( CDCl3 , 300 MHz) δ: 8.19 (d, J=8.7 Hz, 1H), 7.37 (d, J=3.6 Hz, 1H), 6.54 (d, J=3.6 Hz, 1H), 5.64 (s, 2H), 3.58 (t, J=8.1 Hz, 2H), 0.98-0.93 (t, J=8.1 Hz, 2H), 0.00 (s, 9H).
Synthesis of 5-bromo-6-(3,3-diethoxypropoxy)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridine: Into a 250 mL round bottom flask purged and maintained with an inert atmosphere of nitrogen was placed 3,3-diethoxypropan-1-ol (2.6 g, 17.38 mmol, 1.5 equiv), THF (50 mL). This was followed by portionwise addition of NaH (930 mg, 38.75 mmol, 3.35 equiv) at 0° C. The resulting solution was stirred at 25° C. for 30 min. To this was added dropwise a solution of 5-bromo-6-fluoro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridine (4 g, 11.58 mmol, 1 equiv) in THF (10 mL) at 0° C. with stirring. The resulting solution was stirred at 25° C. for 6 hours. The reaction was then quenched by adding 500 ml of aqueous NH 4 Cl. The resulting solution was extracted with 2×200 mL of ethyl acetate. The resulting mixture was washed with 1×500 ml of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied to a silica gel column using ethyl acetate/petroleum ether (1:16). This gave 4 g (72.92%) of 5-bromo-6-(3,3-diethoxypropoxy)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridine as a yellow oil. 1H NMR (300 MHz, CDCl 3- d , ppm) δ 8.03 (s, 1H), 7.15 (d, J = 3.6 Hz, 1H), 6.39 (d, J = 3.6 Hz, 1H), 5.57 (s, 2H), 4.88 (t, J = 5.8 Hz, 1H), 4.52 (t, J = 6.2 Hz, 2H), 3.75 (dq, J = 9.4, 7.1 Hz, 2H), 3.64 - 3.45 (m, 4H), 2.18 (q, J = 6.1 Hz, 2H), 1.24 (t, J = 7.1 Hz, 6H), 1.01 - 0.79 (m, 2H), -0.04 (s, 9H). NMR spectra were measured on a Bruker AvanceIII HD equipped with a BBOF probehead.
tert-ブチルN-[6-(3,3-ジエトキシプロポキシ)-1-[[2-(トリメチルシリル)エトキシ]メチル]-1H-ピロロ[2,3-b]ピリジン-5-イル]カルバメートの合成:窒素の不活性雰囲気でパージされ維持された250mL丸底フラスコ中へ、5-ブロモ-6-(3,3-ジエトキシプロポキシ)-1-[[2-(トリメチルシリル)エトキシ]メチル]-1H-ピロロ[2,3-b]ピリジン(4 g、8.45 mmol、1当量)、ジオキサン(50 mL)、tert-ブチルカルバメート(4.9484 g、42.24 mmol、5.00当量)、Cs2CO3(13.7627 g、42.24 mmol、5.00当量)、XPhos PdG3(1.8 g、2.11 mmol、0.25当量)を入れた。得られる溶液を油浴中で90℃で2時間撹拌した。得られる溶液を500 mlの水で希釈した。得られる溶液を2×200 mLの酢酸エチルで抽出した。得られる混合物を1×500 mlのブラインで洗浄した。混合物を無水硫酸ナトリウム上で乾燥させ、真空下で濃縮した。残渣を、酢酸エチル/石油エーテル(1:16)を使用してシリカゲルカラムに適用した。これにより3.0 g(69.67%)のtert-ブチルN-[6-(3,3-ジエトキシプロポキシ)-1-[[2-(トリメチルシリル)エトキシ]メチル]-1H-ピロロ[2,3-b]ピリジン-5-イル]カルバメートが淡黄色油状物として得られた。LC-MS: (ES, m/z): M+Na=532, R,T= 1.540分.逆相カラム(C18)により保持時間の測定を行った。Shimadzu LCMS 2020; 50×3.0Kinetex 2.6u XB-C18、2.6ミクロン;溶離液A:水(0.05% TFA);溶離液B:アセトニトリル;2.0分間で5%アセトニトリルから100%アセトニトリルまでの直線的グラジエント;オーブン温度40℃;流量:1.5 mL/分。 Synthesis of tert-butyl N-[6-(3,3-diethoxypropoxy)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]carbamate: Into a 250 mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, add 5-bromo-6-(3,3-diethoxypropoxy)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridine (4 g, 8.45 mmol, 1 equiv.), dioxane (50 mL), tert-butyl carbamate (4.9484 g, 42.24 mmol, 5.00 equiv.), Cs2CO3 (13.7627 g, 42.24 mmol, 5.00 equiv.), XPhos PdG3 (1.8 g, 2.11 mmol, 5.00 equiv.), ... 1H-pyrrolo[2,3-b]pyridine (4 g, 8.45 mmol, 1 equiv.), dioxane (50 mL), 1H-pyrrolo[2,3-b]pyridine (4 g, 8.45 mmol, 1 mmol, 0.25 equiv.). The resulting solution was stirred in an oil bath at 90° C. for 2 h. The resulting solution was diluted with 500 ml of water. The resulting solution was extracted with 2×200 mL of ethyl acetate. The resulting mixture was washed with 1×500 ml of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied to a silica gel column using ethyl acetate/petroleum ether (1:16). This gave 3.0 g (69.67%) of tert-butyl N-[6-(3,3-diethoxypropoxy)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]carbamate as a pale yellow oil. LC-MS: (ES, m/z): M+Na=532, R,T= 1.540 min. Retention times were measured using a reversed phase column (C18). Shimadzu LCMS 2020; 50×3.0 Kinetex 2.6u XB-C18, 2.6 micron; Eluent A: water (0.05% TFA); Eluent B: acetonitrile; Linear gradient from 5% acetonitrile to 100% acetonitrile in 2.0 min; Oven temperature 40 °C; Flow rate: 1.5 mL/min.
4-[[2-(トリメチルシリル)エトキシ]メチル]-14-オキサ-2,4,10-トリアザトリシクロ[7.5.0.0^[3,7]]テトラデカ-1(9),2,5,7-テトラエンの合成:250mL丸底フラスコ中へ、tert-ブチルN-[6-(3,3-ジエトキシプロポキシ)-1-[[2-(トリメチルシリル)エトキシ]メチル]-1H-ピロロ[2,3-b]ピリジン-5-イル]カルバメート(3 g、5.89 mmol、1当量)、DCM(120 mL)を入れた。これに続いて、撹拌しながらTFA(24mL)を0℃で滴下して加えた。これに、撹拌しながらトリエチルシラン(6843.7 mg、58.86 mmol、10.00当量)を0℃で滴下して加えた。得られる溶液を℃で30分間撹拌し、次いで室温で30分間撹拌した。得られる溶液を500 mlの水性NaHCO3で希釈した。得られる溶液を2×200 mLのジクロロメタンで抽出した。得られる混合物を1×500 mlのブラインで洗浄した。混合物を無水硫酸ナトリウム上で乾燥させ、真空下で濃縮した。粗生成物をFlash-Prep-HPLCにより以下の条件で精製した(IntelFlash-1):カラム、C18逆相カラム;移動相、A:H2O(0.05%NH3.H2O+0.05%NH4HCO3)、B:CH3CN(15分で15%から75%まで);検出器、220 nm。これにより150 mg(7.98%)の4-[[2-(トリメチルシリル)エトキシ]メチル]-14-オキサ-2,4,10-トリアザトリシクロ[7.5.0.0^[3,7]]テトラデカ-1(9),2,5,7-テトラエンが黒色油状物として得られた。1H NMR (300 MHz, DMSO-d6, ppm) δ 7.42 (s, 1H), 7.35 (d, J = 3.5 Hz, 1H), 6.29 (d, J = 3.5 Hz, 1H), 5.43 (s, 2H), 5.17 (d, J = 3.9 Hz, 1H), 4.15 - 3.98 (m, 2H), 3.57 - 3.40 (m, 2H), 3.18 - 2.96 (m, 2H), 1.91 (d, J = 6.7 Hz, 2H), 0.81 (t, J = 8.0 Hz, 2H), -0.09 (s, 9H).BBOFのプローブヘッドを備えたBruker AvanceIII HD 300MHzでNMRスペクトルの測定を行った。 Synthesis of 4-[[2-(trimethylsilyl)ethoxy]methyl]-14-oxa-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradeca-1(9),2,5,7-tetraene: In a 250 mL round bottom flask was placed tert-butyl N-[6-(3,3-diethoxypropoxy)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]carbamate (3 g, 5.89 mmol, 1 equiv.), DCM (120 mL). This was followed by the dropwise addition of TFA (24 mL) at 0° C. with stirring. To this was added triethylsilane (6843.7 mg, 58.86 mmol, 10.00 equiv.) dropwise at 0° C. with stirring. The resulting solution was stirred at °C for 30 min, then at room temperature for 30 min. The resulting solution was diluted with 500 ml of aqueous NaHCO 3. The resulting solution was extracted with 2×200 mL of dichloromethane. The resulting mixture was washed with 1×500 ml of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by Flash-Prep-HPLC (IntelFlash-1) with the following conditions: column, C18 reverse phase column; mobile phase, A: H 2 O (0.05% NH 3 .H 2 O+0.05% NH 4 HCO 3 ), B: CH 3 CN (15% to 75% in 15 min); detector, 220 nm. This gave 150 mg (7.98%) of 4-[[2-(trimethylsilyl)ethoxy]methyl]-14-oxa-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradeca-1(9),2,5,7-tetraene as a black oil. 1H NMR (300 MHz, DMSO-d 6, ppm) δ 7.42 (s, 1H), 7.35 (d, J = 3.5 Hz, 1H), 6.29 (d, J = 3.5 Hz, 1H), 5.43 (s, 2H), 5.17 (d, J = 3.9 Hz, 1H), 4.15 - 3.98 (m, 2H), 3.57 - 3.40 (m, 2H), 3.18 - 2.96 (m, 2H), 1.91 (d, J = 6.7 Hz, 2H), 0.81 (t, J = 8.0 Hz, 2H), -0.09 (s, 9H). NMR spectra were recorded on a Bruker AvanceIII HD 300MHz equipped with a BBOF probehead.
[実施例1-5]
13-メチル-4-[[2-(トリメチルシリル)エトキシ]メチル]-14-オキサ-2,4,10-トリアザトリシクロ[7.5.0.0^[3,7]]テトラデカ-1(9),2,5,7-テトラエンの調製
N-(3-ヒドロキシブチル)-4-メチルベンゼン-1-スルホンアミドの合成。窒素の不活性雰囲気でパージされ維持された250mL丸底フラスコ中へ、4-アミノブタン-2-オール塩酸塩(4 g、31.847 mmol、1当量)、DCM(40 mL)、TEA(3.56 g、35.181 mmol、1.10当量)を入れた。これに続いて4-メチルベンゼン-1-塩化スルホニル(6.08 g、31.893 mmol、1.00当量)を0℃で少しずつ加えた。得られる溶液を25℃で2時間撹拌した。得られる混合物を真空下で濃縮した。残渣を、酢酸エチル/石油エーテル(1:1)を使用してシリカゲルカラムに適用した。これにより4.4 g(56.78%)のN-(3-ヒドロキシブチル)-4-メチルベンゼン-1-スルホンアミドが無色油状物として得られた。1H NMR (300 MHz, CDCl3-d, ppm) δ 7.82 - 7.73 (d, J = 9.0 Hz, 2H), 7.39 - 7.30 (d, J = 9.0 Hz, 2H), 4.06 - 3.82 (m, 1H), 3.24 - 3.16 (m, 1H), 3.06 - 3.00 (m, 1H), 2.45 (s, 3H), 1.70 - 1.55 (m, 2H), 1.20 (d, J = 6.2 Hz, 3H).
[Examples 1-5]
Preparation of 13-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-14-oxa-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradeca-1(9),2,5,7-tetraene
Synthesis of N-(3-hydroxybutyl)-4-methylbenzene-1-sulfonamide. In a 250 mL round bottom flask purged and maintained with an inert atmosphere of nitrogen, 4-aminobutan-2-ol hydrochloride (4 g, 31.847 mmol, 1 equiv.), DCM (40 mL), TEA (3.56 g, 35.181 mmol, 1.10 equiv.) were added. This was followed by the addition of 4-methylbenzene-1-sulfonyl chloride (6.08 g, 31.893 mmol, 1.00 equiv.) in portions at 0° C. The resulting solution was stirred at 25° C. for 2 h. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column using ethyl acetate/petroleum ether (1:1). This gave 4.4 g (56.78%) of N-(3-hydroxybutyl)-4-methylbenzene-1-sulfonamide as a colorless oil. 1H NMR (300 MHz, CDCl3 -d , ppm) δ 7.82 - 7.73 (d, J = 9.0 Hz, 2H), 7.39 - 7.30 (d, J = 9.0 Hz, 2H), 4.06 - 3.82 (m, 1H), 3.24 - 3.16 (m, 1H), 3.06 - 3.00 (m, 1H), 2.45 (s, 3H), 1.70 - 1.55 (m, 2H), 1.20 (d, J = 6.2 Hz, 3H).
N-[3-[(5-ブロモ-1-[[2-(トリメチルシリル)エトキシ]メチル]-1H-ピロロ[2,3-b]ピリジン-6-イル)オキシ]ブチル]-4-メチルベンゼン-1-スルホンアミドの合成。窒素の不活性雰囲気でパージされ維持された250mL三つ口丸底フラスコ中へ、N-(3-ヒドロキシブチル)-4-メチルベンゼン-1-スルホンアミド(4.4 g、18.083 mmol、1.10当量)、THF(60 mL)を入れた。これに続いて、NaH(1.97 g、49.255 mmol、3.00当量、60%)を0℃で少しずつ加えた。得られる溶液を0℃で0.5時間撹拌した。これに、5-ブロモ-6-フルオロ-1-[[2-(トリメチルシリル)エトキシ]メチル]-1H-ピロロ[2,3-b]ピリジン(5.66 g、16.392 mmol、1当量)を加えた。得られる溶液を油浴中で50℃で一晩撹拌した。反応混合物を25℃に冷却した。次いで500 mlのNH4Clを加えることにより、反応をクエンチした。得られる溶液を2×200 mLの酢酸エチルで抽出し、有機層を合わせた。得られる混合物を1×500 mlのブラインで洗浄した。混合物を無水硫酸ナトリウム上で乾燥させ、真空下で濃縮した。残渣を、酢酸エチル/石油エーテル(1:3)を使用してシリカゲルカラムに適用した。これにより6 g(64.37%)のN-[3-[(5-ブロモ-1-[[2-(トリメチルシリル)エトキシ]メチル]-1H-ピロロ[2,3-b]ピリジン-6-イル)オキシ]ブチル]-4-メチルベンゼン-1-スルホンアミドが、無色油状物として得られた。1H NMR (300 MHz, CDCl3-d, ppm) δ 8.04 (s, 1H), 7.74 - 7.63 (m, 2H), 7.23 - 7.11 (m, 3H), 6.41 (d, J = 3.6 Hz, 1H), 5.56 (d, J = 3.3 Hz, 2H), 5.89 - 5.33 (m, 1H), 3.59 - 3.46 (m, 2H), 3.17 (t, J = 6.0 Hz, 2H), 2.37 (s, 3H), 2.08 - 1.78 (m, 2H), 1.37 (d, J = 6.2 Hz, 3H), 0.94 - 0.85 (m, 2H), -0.06 (s, 9H). Synthesis of N-[3-[(5-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-6-yl)oxy]butyl]-4-methylbenzene-1-sulfonamide. Into a 250 mL three-necked round bottom flask purged and maintained with an inert atmosphere of nitrogen was placed N-(3-hydroxybutyl)-4-methylbenzene-1-sulfonamide (4.4 g, 18.083 mmol, 1.10 equiv), THF (60 mL). This was followed by the addition of NaH (1.97 g, 49.255 mmol, 3.00 equiv, 60%) in portions at 0° C. The resulting solution was stirred at 0° C. for 0.5 h. To this was added 5-bromo-6-fluoro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridine (5.66 g, 16.392 mmol, 1 eq). The resulting solution was stirred overnight at 50° C. in an oil bath. The reaction mixture was cooled to 25° C. The reaction was then quenched by adding 500 ml of NH 4 Cl. The resulting solution was extracted with 2×200 mL of ethyl acetate and the organic layers were combined. The resulting mixture was washed with 1×500 ml of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied to a silica gel column using ethyl acetate/petroleum ether (1:3). This gave 6 g (64.37%) of N-[3-[(5-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-6-yl)oxy]butyl]-4-methylbenzene-1-sulfonamide as a colorless oil. 1H NMR (300 MHz, CDCl3 -d , ppm) δ 8.04 (s, 1H), 7.74 - 7.63 (m, 2H), 7.23 - 7.11 (m, 3H), 6.41 (d, J = 3.6 Hz, 1H), 5.56 (d, J = 3.3 Hz, 2H), 5.89 - 5.33 (m, 1H), 3.59 - 3.46 (m, 2H), 3.17 (t, J = 6.0 Hz, 2H), 2.37 (s, 3H), 2.08 - 1.78 (m, 2H), 1.37 (d, J = 6.2 Hz, 3H), 0.94 - 0.85 (m, 2H), -0.06 (s, 9H).
13-メチル-10-(4-メチルベンゼンスルホニル)-4-[[2-(トリメチルシリル)エトキシ]メチル]-14-オキサ-2,4,10-トリアザトリシクロ[7.5.0.0^[3,7]]テトラデカ-1(9),2,5,7-テトラエンの合成。窒素の不活性雰囲気でパージされ維持された250mL丸底フラスコ中へ、N-[3-[(5-ブロモ-1-[[2-(トリメチルシリル)エトキシ]メチル]-1H-ピロロ[2,3-b]ピリジン-6-イル)オキシ]ブチル]-4-メチルベンゼン-1-スルホンアミド(6 g、10.552 mmol、1当量)、DMSO(60 mL)、ピリジン-2-カルボン酸(1.04 g、8.448 mmol、0.80当量)、CuI(2.41 g、12.654 mmol、1.20当量)、K2CO3(4.38 g、31.692 mmol、3.00当量)を入れた。得られる溶液を油浴中で125℃で2日間撹拌した。反応混合物を25℃に冷却した。得られる溶液を500 mlの水で希釈した。得られる溶液を3×200 mLの酢酸エチルで抽出し、有機層を合わせた。得られる混合物を2×1000mlのブラインで洗浄した。混合物を無水硫酸ナトリウム上で乾燥させ、真空下で濃縮した。残渣を、酢酸エチル/石油エーテル(1:3)を使用してシリカゲルカラムに適用した。これにより2.8 g(54.41%)の13-メチル-10-(4-メチルベンゼンスルホニル)-4-[[2-(トリメチルシリル)エトキシ]メチル]-14-オキサ-2,4,10-トリアザトリシクロ[7.5.0.0^[3,7]]テトラデカ-1(9),2,5,7-テトラエンが黄色油状物として得られた。1H NMR (300 MHz, CDCl3-d, ppm) δ 8.10 (s, 1H), 7.53 - 7.40 (m, 2H), 7.30 (d, J = 3.6 Hz, 1H), 7.24 - 7.12 (m, 2H), 6.50 (d, J = 3.6 Hz, 1H), 5.65 (d, J = 10.7 Hz, 1H), 5.49 (d, J = 10.7 Hz, 1H), 4.37 - 4.23 (m, 1H), 3.94 - 3.80 (m, 1H), 3.62 - 3.36 (m, 3H), 2.37 (s, 3H), 1.89 - 1.64 (m, 2H), 1.23 (d, J = 6.3 Hz, 3H), 1.01 - 0.76 (m, 2H), -0.07 (s, 9H). Synthesis of 13-methyl-10-(4-methylbenzenesulfonyl)-4-[[2-(trimethylsilyl)ethoxy]methyl]-14-oxa-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradeca-1(9),2,5,7-tetraene. Into a 250 mL round bottom flask purged and maintained with an inert atmosphere of nitrogen was placed N-[3-[(5-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-6-yl)oxy]butyl]-4-methylbenzene-1-sulfonamide (6 g, 10.552 mmol, 1 equiv.), DMSO (60 mL), pyridine-2-carboxylic acid (1.04 g, 8.448 mmol, 0.80 equiv.), CuI (2.41 g, 12.654 mmol, 1.20 equiv.), K2CO3 (4.38 g, 31.692 mmol, 3.00 equiv.). The resulting solution was stirred in an oil bath at 125° C. for 2 days. The reaction mixture was cooled to 25° C. The resulting solution was diluted with 500 ml of water. The resulting solution was extracted with 3×200 mL of ethyl acetate and the organic layers were combined. The resulting mixture was washed with 2×1000 ml of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied to a silica gel column using ethyl acetate/petroleum ether (1:3). This gave 2.8 g (54.41%) of 13-methyl-10-(4-methylbenzenesulfonyl)-4-[[2-(trimethylsilyl)ethoxy]methyl]-14-oxa-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradeca-1(9),2,5,7-tetraene as a yellow oil. 1H NMR (300 MHz, CDCl3 -d , ppm) δ 8.10 (s, 1H), 7.53 - 7.40 (m, 2H), 7.30 (d, J = 3.6 Hz, 1H), 7.24 - 7.12 (m, 2H), 6.50 (d, J = 3.6 Hz, 1H), 5.65 (d, J = 10.7 Hz, 1H), 5.49 (d, J = 10.7 Hz, 1H), 4.37 - 4.23 (m, 1H), 3.94 - 3.80 (m, 1H), 3.62 - 3.36 (m, 3H), 2.37 (s, 3H), 1.89 - 1.64 (m, 2H), 1.23 (d, J = 6.3 Hz, 3H), 1.01 - 0.76 (m, 2H), -0.07 (s, 9H).
13-メチル-4-[[2-(トリメチルシリル)エトキシ]メチル]-14-オキサ-2,4,10-トリアザトリシクロ[7.5.0.0^[3,7]]テトラデカ-1(9),2,5,7-テトラエンの合成。窒素の不活性雰囲気でパージされ維持された250mL丸底フラスコ中へ、Na(793.5 mg、34.51 mmol、6.01当量)、ナフタレン(4.42 g、34.48 mmol、6.01当量)、DME(20 mL)を入れた。Na/ナフタレンの形成が完了するまで、混合物を室温で40分間撹拌した。窒素の不活性雰囲気でパージされ維持された別の250mL丸底フラスコに、13-メチル-10-(4-メチルベンゼンスルホニル)-4-[[2-(トリメチルシリル)エトキシ]メチル]-14-オキサ-2,4,10-トリアザトリシクロ[7.5.0.0^[3,7]]テトラデカ-1(9),2,5,7-テトラエン(2.8 g、5.741 mmol、1当量)、THF(20 mL)を入れた。これに続いて上記溶液を-78℃で加えた。得られる溶液を室温で3時間撹拌した。次いで500 mLのNH4Clを加えることにより反応をクエンチした。得られる溶液を3×200 mLの酢酸エチルで抽出し、有機層を合わせた。得られる混合物を1×500 mlのブラインで洗浄した。混合物を無水硫酸ナトリウム上で乾燥させ、真空下で濃縮した。残渣を、酢酸エチル/石油エーテル(1:3)を使用してシリカゲルカラムに適用した。これにより1.2 g(62.67%)の13-メチル-4-[[2-(トリメチルシリル)エトキシ]メチル]-14-オキサ-2,4,10-トリアザトリシクロ[7.5.0.0^[3,7]]テトラデカ-1(9),2,5,7-テトラエンが黄色油状物として得られた。1H NMR (300 MHz, DMSO-d6, ppm) δ 7.43 - 7.26 (m, 2H), 6.27 (d, J = 3.5 Hz, 1H), 5.43 (d, J = 3.4 Hz, 2H), 5.13 (s, 1H), 4.14 - 4.04 (m, 1H), 3.58 - 3.39 (m, 3H), 3.28 - 3.10 (m, 1H), 2.95 - 2.77 (m, 1H), 2.09 - 1.85 (m, 1H), 1.85 - 1.64 (m, 1H), 1.37 (d, J = 6.3 Hz, 3H), 0.88 - 078 (m, 2H), -0.09 (s, 9H). Synthesis of 13-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-14-oxa-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradeca-1(9),2,5,7-tetraene. Into a 250 mL round bottom flask purged and maintained with an inert atmosphere of nitrogen was placed Na (793.5 mg, 34.51 mmol, 6.01 equiv), naphthalene (4.42 g, 34.48 mmol, 6.01 equiv), and DME (20 mL). The mixture was stirred at room temperature for 40 min until the formation of Na/naphthalene was complete. In another 250 mL round bottom flask, purged and maintained with an inert atmosphere of nitrogen, was charged with 13-methyl-10-(4-methylbenzenesulfonyl)-4-[[2-(trimethylsilyl)ethoxy]methyl]-14-oxa-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradeca-1(9),2,5,7-tetraene (2.8 g, 5.741 mmol, 1 equiv.), THF (20 mL). This was followed by the addition of the above solution at -78°C. The resulting solution was stirred at room temperature for 3 hours. The reaction was then quenched by adding 500 mL of NH 4 Cl. The resulting solution was extracted with 3×200 mL of ethyl acetate and the organic layers were combined. The resulting mixture was washed with 1×500 ml of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied to a silica gel column using ethyl acetate/petroleum ether (1:3). This gave 1.2 g (62.67%) of 13-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-14-oxa-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradeca-1(9),2,5,7-tetraene as a yellow oil. 1H NMR (300 MHz, DMSO-d 6, ppm) δ 7.43 - 7.26 (m, 2H), 6.27 (d, J = 3.5 Hz, 1H), 5.43 (d, J = 3.4 Hz, 2H), 5.13 (s, 1H), 4.14 - 4.04 (m, 1H), 3.58 - 3.39 (m, 3H), 3.28 - 3.10 (m, 1H), 2.95 - 2.77 (m, 1H), 2.09 - 1.85 (m, 1H), 1.85 - 1.64 (m, 1H), 1.37 (d, J = 6.3 Hz, 3H), 0.88 - 078 (m, 2H), -0.09 (s, 9H).
13-メチル-4-[[2-(トリメチルシリル)エトキシ]メチル]-14-オキサ-2,4,10-トリアザトリシクロ[7.5.0.0^[3,7]]テトラデカ-1(9),2,5,7-テトラエンの合成。粗生成物(0.5 g)をChiral-Prep-HPLCにより以下の条件で精製した:装置名称:SHIMADZU LC-20AD、LCパラメーター:ポンプモード:バイナリーグラジエント、ポンプBのStart Cone:50.0%、全流量:15 mL/分、相A:n-ヘキサン(0.1% DEA)、相B:エタノール、カラム名称:CHIRALpak IA-3、長さ:50 mm、内径:4.6 mm、粒径:3.0 um、カラム温度:25℃、PDA モデル:SPD-M20A、波長:190 nm~500 nm。これにより、220 mg(ピーク1)[a]=-6.78°(CH2Cl2中C=0.129 g/100 mL、T=27℃)の(13R又はS)-13-メチル-4-[[2-(トリメチルシリル)エトキシ]メチル]-14-オキサ-2,4,10-トリアザトリシクロ[7.5.0.0^[3,7]]テトラデカ-1(9),2,5,7-テトラエンが黄色油状物として及び230 mg(ピーク2)[a]=+11.84°(CH2Cl2中C=0.106 g/100 mL、T=27℃)の(13S又はR)-13-メチル-4-[[2-(トリメチルシリル)エトキシ]メチル]-14-オキサ-2,4,10-トリアザトリシクロ[7.5.0.0^[3,7]]テトラデカ-1(9),2,5,7-テトラエンが黄色油状物として得られた。 Synthesis of 13-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-14-oxa-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradeca-1(9),2,5,7-tetraene. The crude product (0.5 g) was purified by Chiral-Prep-HPLC under the following conditions: Instrument name: SHIMADZU LC-20AD, LC parameters: Pump mode: binary gradient, Start Cone of Pump B: 50.0%, Total flow rate: 15 mL/min, Phase A: n-hexane (0.1% DEA), Phase B: ethanol, Column name: CHIRALpak IA-3, Length: 50 mm, Inner diameter: 4.6 mm, Particle size: 3.0 um, Column temperature: 25°C, PDA model: SPD-M20A, Wavelength: 190 nm to 500 nm. This gave 220 mg (peak 1) [a] = -6.78° (C in CH2Cl2 = 0.129 g/100 mL, T = 27°C) of (13R or S)-13-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-14-oxa-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradeca-1(9),2,5,7-tetraene as a yellow oil and 230 mg (peak 2) [a] = +11.84° (C in CH2Cl2 = 0.106 g/100 mL, T = 27 °C) of 13R or S mL, T = 27 °C) of (13S or R)-13-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-14-oxa-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradeca-1(9),2,5,7-tetraene was obtained as a yellow oil.
[実施例2]
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3'2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミドの調製
メチル2-ブロモ-4-(4-[[2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エン-1-イル]メチル]ピペラジン-1-イル)ベンゾエートの合成:250mL丸底フラスコ中へ、実施例1-1、すなわち1-[[2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エン-1-イル]メチル]ピペラジン(15.09 g、47.32 mmol、1.00当量)のDMA(150 mL)、DIEA(12.9 g、99.81 mmol、2.00当量)、メチル2-ブロモ-4-フルオロベンゾエート(11.6 g、49.78 mmol、1.00当量)中の溶液を入れた。得られる溶液を100度で12時間撹拌した。反応混合物を室温に冷却した。次いで50 mLの水を加えることにより反応をクエンチした。得られる溶液を3×100 mLの酢酸エチルで抽出し、有機層を合わせた。得られる混合物を3×100 mLのブラインで洗浄した。混合物を無水硫酸ナトリウム上で乾燥させ、次いでろ過し、真空下で濃縮した。残渣を、酢酸エチル/石油エーテル(0:1~1:5)を使用してシリカゲルカラムに適用した。これにより7 g(粗製)のメチル2-ブロモ-4-(4-[[2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エン-1-イル]メチル]ピペラジン-1-イル)ベンゾエートが黄色油状物として得られた。LC-MS: (ES, m/z): M+1=533, 531.
[Example 2]
Preparation of 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3'2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide Synthesis of methyl 2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)benzoate: Into a 250 mL round bottom flask was placed a solution of Example 1-1, i.e. 1-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazine (15.09 g, 47.32 mmol, 1.00 equiv.) in DMA (150 mL), DIEA (12.9 g, 99.81 mmol, 2.00 equiv.), and methyl 2-bromo-4-fluorobenzoate (11.6 g, 49.78 mmol, 1.00 equiv.). The resulting solution was stirred at 100° C. for 12 hours. The reaction mixture was cooled to room temperature. The reaction was then quenched by adding 50 mL of water. The resulting solution was extracted with 3×100 mL of ethyl acetate and the organic layers were combined. The resulting mixture was washed with 3×100 mL of brine. The mixture was dried over anhydrous sodium sulfate, then filtered and concentrated under vacuum. The residue was applied to a silica gel column using ethyl acetate/petroleum ether (0:1 to 1:5). This gave 7 g (crude) of methyl 2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)benzoate as a yellow oil. LC-MS: (ES, m/z): M+1=533, 531.
メチル4-(4-[[2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エン-1-イル]メチル]ピペラジン-1-イル)-2-(4-[[2-(トリメチルシリル)エトキシ]メチル]-14-オキサ-2,4,10-トリアザトリシクロ[7.5.0.0^[3,7]]テトラデカ-1(9),2,5,7-テトラエン-10-イル)ベンゾエートの合成:窒素の不活性雰囲気でパージされ維持された100 mL丸底フラスコ中へ、メチル2-ブロモ-4-(4-[[2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エン-1-イル]メチル]ピペラジン-1-イル)ベンゾエート(999.0 mg、1.88 mmol、4.00当量)、トルエン(20 mL)、4-[[2-(トリメチルシリル)エトキシ]メチル]-14-オキサ-2,4,10-トリアザトリシクロ[7.5.0.0^[3,7]]テトラデカ-1(9),2,5,7-テトラエン(150 mg、0.47 mmol、1当量)、Cs2CO3(764.9 mg、2.35 mmol、5当量)、キサントホス(XantPhos) Pd 2G(333.2 mg、0.38 mmol、0.8当量)を入れた。得られる溶液を110℃で一晩撹拌した。得られる溶液を300 mLの水で希釈した。得られる溶液を2×100 mLの酢酸エチルで抽出した。得られる混合物を1×300 mLのブラインで洗浄した。混合物を無水硫酸ナトリウム上で乾燥させ、真空下で濃縮した。残渣を、酢酸エチル/石油エーテル(1:2)を使用してシリカゲルカラムに適用した。これにより、200 mg(55.29%)のメチル4-(4-[[2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エン-1-イル]メチル]ピペラジン-1-イル)-2-(4-[[2-(トリメチルシリル)エトキシ]メチル]-14-オキサ-2,4,10-トリアザトリシクロ[7.5.0.0^[3,7]]テトラデカ-1(9),2,5,7-テトラエン-10-イル)ベンゾエートが黄色固体として得られた。LC-MS: (ES, m/z): M+H=769, R,T= 3.076分.逆相カラム(C18)により保持時間の測定を行った。Shimadzu LCMS 2020; 50×3.0 Shim-パック XR-ODS、2.2ミクロン;溶離液A:水(0.05% TFA);溶離液B:アセトニトリル;5.0分で5%アセトニトリルから100%アセトニトリルまでの直線的グラジエント;オーブン温度40℃;流量:1.5 mL/分。 Synthesis of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-(4-[[2-(trimethylsilyl)ethoxy]methyl]-14-oxa-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradec-1(9),2,5,7-tetraen-10-yl)benzoate: Into a 100 mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, add methyl 2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)benzoate (999.0 mg, 1.88 mmol, 4.00 equiv.), toluene (20 1 mL), 4-[[2-(trimethylsilyl)ethoxy]methyl]-14-oxa-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradeca-1(9),2,5,7-tetraene (150 mg, 0.47 mmol, 1 equiv), Cs2CO3 ( 764.9 mg, 2.35 mmol, 5 equiv), and XantPhos Pd 2G (333.2 mg, 0.38 mmol, 0.8 equiv). The resulting solution was stirred at 110 °C overnight. The resulting solution was diluted with 300 mL of water. The resulting solution was extracted with 2 × 100 mL of ethyl acetate. The resulting mixture was washed with 1 × 300 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied to a silica gel column using ethyl acetate/petroleum ether (1:2). This gave 200 mg (55.29%) of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-(4-[[2-(trimethylsilyl)ethoxy]methyl]-14-oxa-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradec-1(9),2,5,7-tetraen-10-yl)benzoate as a yellow solid. LC-MS: (ES, m/z): M+H=769, R,T= 3.076 min. Retention time was measured using a reversed phase column (C18). Shimadzu LCMS 2020; 50×3.0 Shim-pack XR-ODS, 2.2 micron; Eluent A: water (0.05% TFA); Eluent B: acetonitrile; linear gradient from 5% acetonitrile to 100% acetonitrile in 5.0 min; oven temperature 40 °C; flow rate: 1.5 mL/min.
メチル4-(4-[[2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エン-1-イル]メチル]ピペラジン-1-イル)-2-[14-オキサ-2,4,10-トリアザトリシクロ[7.5.0.0^[3,7]]テトラデカ-1(9),2,5,7-テトラエン-10-イル]ベンゾエートの合成:40 mLバイアル中へ、メチル4-(4-[[2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エン-1-イル]メチル]ピペラジン-1-イル)-2-(4-[[2-(トリメチルシリル)エトキシ]メチル]-14-オキサ-2,4,10-トリアザトリシクロ[7.5.0.0^[3,7]]テトラデカ-1(9),2,5,7-テトラエン-10-イル)ベンゾエート(200 mg、0.26 mmol、1当量)、THF(20 mL)、TBAF.3H2O(2.5 g)、エタン-1,2-ジアミン(1.5 g、24.96 mmol、96.15当量)を入れた。得られる溶液を油浴中で70℃で2晩撹拌した。得られる溶液を200 mLの水で希釈した。得られる溶液を3×30 mLの酢酸エチルで抽出した。得られる混合物を2×200 mLのブラインで洗浄した。混合物を無水硫酸ナトリウム上で乾燥させ、真空下で濃縮した。残渣を、酢酸エチル/石油エーテル(2:1)を使用してシリカゲルカラムに適用した。これにより130 mg(78.22%)のメチル4-(4-[[2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エン-1-イル]メチル]ピペラジン-1-イル)-2-[14-オキサ-2,4,10-トリアザトリシクロ[7.5.0.0^[3,7]]テトラデカ-1(9),2,5,7-テトラエン-10-イル]ベンゾエートが淡黄色固体として得られた。LC-MS: (ES, m/z): M+H=639, R,T= 1.388分.逆相カラム(C18)により保持時間の測定を行った。Shimadzu LCMS 2020; 50×3.0 Shim-パック XR-ODS、2.2ミクロン;溶離液A:水(0.05% TFA);溶離液B:アセトニトリル;2.6分で5%アセトニトリルから100%アセトニトリルまでの直線的グラジエント;オーブン温度40℃;流量:1.5 mL/分。 Synthesis of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[14-oxa-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradec-1(9),2,5,7-tetraen-10-yl]benzoate: In a 40 mL vial, add 200 mg of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-(4-[[2-(trimethylsilyl)ethoxy]methyl]-14-oxa-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradec-1(9),2,5,7-tetraen-10-yl)benzoate (0.26 mg, 1 mL). The resulting solution was stirred in an oil bath at 70° C. for 2 nights. The resulting solution was diluted with 200 mL of water. The resulting solution was extracted with 3×30 mL of ethyl acetate. The resulting mixture was washed with 2×200 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied to a silica gel column using ethyl acetate/petroleum ether (2:1). This gave 130 mg (78.22%) of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[14-oxa-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradec-1(9),2,5,7-tetraen-10-yl]benzoate as a pale yellow solid. LC-MS: (ES, m/z): M+H=639, R,T= 1.388 min. Retention time was measured using a reversed phase column (C18). Shimadzu LCMS 2020; 50×3.0 Shim-pack XR-ODS, 2.2 micron; Eluent A: water (0.05% TFA); Eluent B: acetonitrile; linear gradient from 5% acetonitrile to 100% acetonitrile in 2.6 min; oven temperature 40 °C; flow rate: 1.5 mL/min.
4-(4-[[2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エン-1-イル]メチル]ピペラジン-1-イル)-2-[14-オキサ-2,4,10-トリアザトリシクロ[7.5.0.0^[3,7]]テトラデカ-1(9),2,5,7-テトラエン-10-イル]安息香酸の合成:40-mLバイアル中へ、メチル4-(4-[[2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エン-1-イル]メチル]ピペラジン-1-イル)-2-[14-オキサ-2,4,10-トリアザトリシクロ[7.5.0.0^[3,7]]テトラデカ-1(9),2,5,7-テトラエン-10-イル]ベンゾエート(130 mg、0.20 mmol、1当量)、MeOH(6 mL)、THF(6 mL)、H20(2 mL)、NaOH(81.2 mg、2.03 mmol、10.00当量)を入れた。得られる溶液を油浴中で60℃で一晩撹拌した。得られる混合物を真空下で濃縮した。HCl(2モル/L)で溶液のpH値を5~6に調整した。得られる溶液を2×50 mLのジクロロメタン/MeOH(v:v=10:l)で抽出した。得られる混合物を2×200 mLのブラインで洗浄した。混合物を無水硫酸ナトリウム上で乾燥させ、真空下で濃縮した。これにより80 mg(62.92%)の4-(4-[[2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エン-1-イル]メチル]ピペラジン-1-イル)-2-[14-オキサ-2,4,10-トリアザトリシクロ[7.5.0.0^[3,7]]テトラデカ-1(9),2,5,7-テトラエン-10-イル]安息香酸が淡黄色固体として得られた。LC-MS: (ES, m/z): M+H=625, R,T= 1.336分.逆相カラム(C18)により保持時間の測定を行った。Shimadzu LCMS 2020; 50×3.0 Shim-パック XR-ODS、2.2ミクロン;溶離液A:水(0.05% TFA);溶離液B:アセトニトリル;2.6分で5%アセトニトリルから100%アセトニトリルまでの直線的グラジエント;オーブン温度40℃;流量:1.5 mL/分。 Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[14-oxa-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradec-1(9),2,5,7-tetraen-10-yl]benzoic acid: In a 40-mL vial, add methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[14-oxa-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradec-1(9),2,5,7-tetraen-10-yl]benzoate (130 mg, 0.20 mmol, 1 equiv.), MeOH (6 mL), THF (6 The resulting solution was stirred overnight at 60° C. in an oil bath. The resulting mixture was concentrated under vacuum. The pH value of the solution was adjusted to 5-6 with HCl (2 mol/L). The resulting solution was extracted with 2×50 mL of dichloromethane/MeOH (v:v=10:l). The resulting mixture was washed with 2×200 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This gave 80 mg (62.92%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[14-oxa-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradec-1(9),2,5,7-tetraen-10-yl]benzoic acid as a pale yellow solid. LC-MS: (ES, m/z): M+H=625, R,T= 1.336 min. Retention time was measured using a reversed phase column (C18). Shimadzu LCMS 2020; 50×3.0 Shim-pack XR-ODS, 2.2 micron; Eluent A: water (0.05% TFA); Eluent B: acetonitrile; linear gradient from 5% acetonitrile to 100% acetonitrile in 2.6 min; oven temperature 40 °C; flow rate: 1.5 mL/min.
4-(4-[[2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エン-1-イル]メチル]ピペラジン-1-イル)-N-(3-ニトロ-4-[[(オキサン-4-イル)メチル]アミノ]ベンゼンスルホニル)-2-[14-オキサ-2,4,10-トリアザトリシクロ[7.5.0.0^[3,7]]テトラデカ-1(9),2,5,7-テトラエン-10-イル]ベンズアミドの合成:40mL丸底フラスコ中へ、4-(4-[[2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エン-1-イル]メチル]ピペラジン-1-イル)-2-[14-オキサ-2,4,10-トリアザトリシクロ[7.5.0.0^[3,7]]テトラデカ-1(9),2,5,7-テトラエン-10-イル]安息香酸(50 mg、0.08 mmol、1当量)、DCM(3 mL)、3-ニトロ-4-[[(オキサン-4-イル)メチル]アミノ]ベンゼン-1-スルホンアミド(25.2 mg、0.08 mmol、1.00当量)、EDCI(30.6 mg、0.16 mmol、2当量)、DMAP(39.0 mg、0.32 mmol、4当量)を入れた。得られる溶液を25度で一晩撹拌した。得られる混合物を真空下で濃縮した。残渣を、ジクロロメタン/メタノール(10:1)を使用してシリカゲルカラムに適用した。粗生成物をFlash-Prep-HPLCにより以下の条件で精製した(IntelFlash-1):カラム、C18逆相カラム;移動相、水(10 MMOL/LNH4HCO3+0.05%NH3.H2O)及びCH3CN(20.0%CH3CNを30分で90.0%まで上昇させる);検出器、UV 220 nm。これにより19.1 mg(25.90%)の4-(4-[[2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エン-1-イル]メチル]ピペラジン-1-イル)-N-(3-ニトロ-4-[[(オキサン-4-イル)メチル]アミノ]ベンゼンスルホニル)-2-[14-オキサ-2,4,10-トリアザトリシクロ[7.5.0.0^[3,7]]テトラデカ-1(9),2,5,7-テトラエン-10-イル]ベンズアミドが黄色固体として得られた。LC-MS: (ES, m/z): M+1=923, R,T= 3.463分.逆相カラム(C18)により保持時間の測定を行った。Shimadzu LCMS 2020; 50×3.0 Agilent Poroshell HPH-C18、2.7 um;溶離液A:水(0.05%アンモニア水);溶離液B:アセトニトリル;7.0分で5%アセトニトリルから95%アセトニトリルまでの直線的グラジエント;オーブン温度40℃;流量:1.5 mL/分。1H NMR (300 MHz, DMSO-d6, ppm) δ 11.91 (s, 1H), 11.26 (s, 1H), 8.56 (s, 1H), 8.47 (d, J = 2.1 Hz, 1H), 7.61 (d, J = 9.0 Hz, 1H), 7.48 (d, J = 9.2 Hz, 1H), 7.37 (d, J = 8.3 Hz, 2H), 7.20 (s, 1H), 7.07 (d, J = 8.3 Hz, 2H), 6.99 - 6.83 (m, 2H), 6.76 (d, J = 29.2 Hz, 2H), 6.14 (s, 1H), 4.21 (s, 2H), 3.85 (d, J = 9.3 Hz, 2H), 3.52 (s, 2H), 3.30 - 3.14 (m, 8H), 2.79 (s, 1H), 2.23 (d, J = 20.0 Hz, 5H), 1.99 (s, 4H), 1.85 (s, 1H), 1.61 (d, J = 11.3 Hz, 2H), 1.42 (s, 2H), 1.25 (s, 2H), 1.03 - 0.79 (m, 6H).BBOFのプローブヘッドを備えたBruker AvanceIII HD 300MHzでNMRスペクトルの測定を行った。 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-N-(3-nitro-4-[[(oxan-4-yl)methyl]amino]benzenesulfonyl)-2-[14-oxa-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradeca-1(9),2,5,7-tetraene Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[14-oxa-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradec-1(9),2,5,7-tetraen-10-yl]benzoic acid (50 mg, 0.08 mmol, 1 equiv.), DCM (3 mL), 3-nitro-4-[[(oxan-4-yl)methyl]amino]benzene-1-sulfonamide (25.2 mg, 0.08 mmol, 1.00 equiv.), EDCI (30.6 mg, 0.16 mmol, 2 equiv.), DMAP (39.0 mg, 0.32 mmol, 4 equiv.) were added to a 40 mL round bottom flask. The resulting solution was stirred at 25° overnight. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column using dichloromethane/methanol (10:1). The crude product was purified by Flash-Prep-HPLC under the following conditions (IntelFlash-1): column, C18 reverse phase column; mobile phase, water ( 10 MMOL/ LNH4HCO3 + 0.05% NH3.H2O ) and CH3CN (20.0% CH3CN increased to 90.0% in 30 min); detector, UV 220 nm . This gave 19.1 mg (25.90%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-N-(3-nitro-4-[[(oxan-4-yl)methyl]amino]benzenesulfonyl)-2-[14-oxa-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradec-1(9),2,5,7-tetraen-10-yl]benzamide as a yellow solid. LC-MS: (ES, m/z): M+1=923, R,T= 3.463 min. Retention time was measured using a reversed phase column (C18). Shimadzu LCMS 2020; 50×3.0 Agilent Poroshell HPH-C18, 2.7 um; Eluent A: water (0.05% aqueous ammonia); Eluent B: acetonitrile; linear gradient from 5% acetonitrile to 95% acetonitrile in 7.0 min; oven temperature 40 °C; flow rate: 1.5 mL/min. 1H NMR (300 MHz, DMSO-d 6, ppm) δ 11.91 (s, 1H), 11.26 (s, 1H), 8.56 (s, 1H), 8.47 (d, J = 2.1 Hz, 1H), 7.61 (d, J = 9.0 Hz, 1H), 7.48 (d, J = 9.2 Hz, 1H), 7.37 (d, J = 8.3 Hz, 2H), 7.20 (s, 1H), 7.07 (d, J = 8.3 Hz, 2H), 6.99 - 6.83 (m, 2H), 6.76 (d, J = 29.2 Hz, 2H), 6.14 (s, 1H), 4.21 (s, 2H), 3.85 (d, J = 9.3 Hz, 2H), 3.52 (s, 2H), 3.30 - 3.14 (m, 8H), 2.79 (s, 1H), 2.23 (d, J = 20.0 Hz, 5H), 1.99 (s, 4H), 1.85 (s, 1H), 1.61 (d, J = 11.3 Hz, 2H), 1.42 (s, 2H), 1.25 (s, 2H), 1.03 - 0.79 (m, 6H). NMR spectra were recorded on a Bruker AvanceIII HD 300 MHz with a BBOF probehead.
[実施例3]
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3'2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-(((4-フルオロテトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミドの調製
40mLバイアル中へ、4-(4-[[2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エン-1-イル]メチル]ピペラジン-1-イル)-2-[14-オキサ-2,4,10-トリアザトリシクロ[7.5.0.0^[3,7]]テトラデカ-1(9),2,5,7-テトラエン-10-イル]安息香酸(80 mg、0.13 mmol、1当量)、DCM(3mL)、4-[[(4-フルオロオキサン-4-イル)メチル]アミノ]-3-ニトロベンゼン-1-スルホンアミド(42.6 mg、0.13 mmol、1.00当量)、EDCI(49.0 mg、0.26 mmol、2当量)、DMAP(62.4 mg、0.51 mmol、4当量)を入れた。得られる溶液を25℃で一晩撹拌した。得られる混合物を真空下で濃縮した。粗生成物を分取HPLCにより以下の条件で精製した(Prep-HPLC-006):カラム、X Bridge Prep C18 OBDカラム、19×150 mm 5 um;移動相、水(10MMOL/LNH4HCO3+0.1%NH3.H2O)及びCH3CN(41.0% CH3CNを6分で61.0%まで上昇させ、95.0%で1分維持し、1分で41.0%まで低下させ、41.0%で1分維持する);検出器、UV 210 nm。これにより17 mg(14.13%)の4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3'2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-(((4-フルオロテトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミドが黄色固体として得られた。LC-MS: (ES, m/z): M+1=940, R,T= 1.583分.逆相カラム(C18)により保持時間の測定を行った。Shimadzu LCMS 2020; 50×3.0 Kinetex 2.6u XB-C18、2.6ミクロン;溶離液A:水(0.05% TFA);溶離液B:アセトニトリル;3.0分で5%アセトニトリルから100%アセトニトリルまでの直線的グラジエント;オーブン温度40℃;流量:1.5 mL/分。1H NMR (300 MHz, DMSO-d6, ppm) δ 11.94 (s, 1H), 11.25 (s, 1H), 8.59 (s, 1H), 8.48 (d, J = 2.3 Hz, 1H), 7.66 (d, J = 9.1 Hz, 1H), 7.47 (d, J = 8.9 Hz, 1H), 7.37 (d, J = 8.2 Hz, 2H), 7.20 (d, J = 3.1 Hz, 1H), 7.07 (dd, J = 8.9, 3.8 Hz, 3H), 6.94 (s, 1H), 6.71 (s, 2H), 6.13 (d, J = 3.1 Hz, 1H), 4.20 (d, J = 6.5 Hz, 2H), 3.80 - 3.70 (m, 3H), 3.68 - 3.60 (m, 1H), 3.58 - 3.45 (m, 4H), 3.25 - 3.05 (m, 4H), 2.83 - 2.69 (m, 2H), 2.33 - 2.10 (m, 6H), 1.98 (s, 4H), 1.84 - 1.68 (m, 4H), 1.49 - 1.35 (m, 2H), 0.95 (s, 6H).BBOFのプローブヘッドを備えたBruker AvanceIII HD 300MHzでNMRスペクトルの測定を行った。
[Example 3]
Preparation of 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3'2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide
Into a 40 mL vial was placed 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[14-oxa-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradec-1(9),2,5,7-tetraen-10-yl]benzoic acid (80 mg, 0.13 mmol, 1 equiv.), DCM (3 mL), 4-[[(4-fluorooxan-4-yl)methyl]amino]-3-nitrobenzene-1-sulfonamide (42.6 mg, 0.13 mmol, 1.00 equiv.), EDCI (49.0 mg, 0.26 mmol, 2 equiv.), and DMAP (62.4 mg, 0.51 mmol, 4 equiv.). The resulting solution was stirred at 25° C. overnight. The resulting mixture was concentrated under vacuum. The crude product was purified by preparative HPLC with the following conditions (Prep-HPLC-006): column, X Bridge Prep C18 OBD column, 19×150 mm 5 um; mobile phase, water (10 mmol/ L NH4HCO3 + 0.1% NH3.H2O ) and CH3CN (41.0% CH3CN ramped to 61.0% in 6 min, held at 95.0% for 1 min, ramped to 41.0% in 1 min , held at 41.0% for 1 min); detector, UV 210 nm. This gave 17 mg (14.13%) of 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3'2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide as a yellow solid. LC-MS: (ES, m/z): M+1=940, R,T= 1.583 min. Retention time was measured using a reverse phase column (C18). Shimadzu LCMS 2020; 50×3.0 Kinetex 2.6u XB-C18, 2.6 micron; Eluent A: water (0.05% TFA); Eluent B: acetonitrile; linear gradient from 5% acetonitrile to 100% acetonitrile in 3.0 min; oven temperature 40 °C; flow rate: 1.5 mL/min. 1H NMR (300 MHz, DMSO-d 6, ppm) δ 11.94 (s, 1H), 11.25 (s, 1H), 8.59 (s, 1H), 8.48 (d, J = 2.3 Hz, 1H), 7.66 (d, J = 9.1 Hz, 1H), 7.47 (d, J = 8.9 Hz, 1H), 7.37 (d, J = 8.2 Hz, 2H), 7.20 (d, J = 3.1 Hz, 1H), 7.07 (dd, J = 8.9, 3.8 Hz, 3H), 6.94 (s, 1H), 6.71 (s, 2H), 6.13 (d, J = 3.1 Hz, 1H), 4.20 (d, J = 6.5 Hz, 2H), 3.80 - 3.70 (m, 3H), 3.68 - 3.60 (m, 1H), 3.58 - 3.45 (m, 4H), 3.25 - 3.05 (m, 4H), 2.83 - 2.69 (m, 2H), 2.33 - 2.10 (m, 6H), 1.98 (s, 4H), 1.84 - 1.68 (m, 4H), 1.49 - 1.35 (m, 2H), 0.95 (s, 6H). NMR spectra were recorded on a Bruker AvanceIII HD 300 MHz equipped with a BBOF probehead.
[実施例4]
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)-2-(4-(トリフルオロメチル)-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミドの調製
4,4,4-トリフルオロ-3-ヒドロキシブタンアミドの合成:50mL丸底フラスコ中へ、MeOH(5mL、4.0M)中のエチル4,4,4-トリフルオロ-3-ヒドロキシブタノエート(500 mg、2.7 mmol、1当量)、NH3を入れた。得られる溶液を60℃で16時間撹拌した。得られる混合物を濃縮した。これにより500 mgの4,4,4-トリフルオロ-3-ヒドロキシブタンアミドが白色固体として得られた。1H NMR (300 MHz, DMSO-d6, ppm) δ 7.62 (ds, 1H), 7.01 (ds, 1H), 3.36-6.34 (m, 1H), 4.27-4.40 (m, 1H), 2.39-2.36 (m, 2H).BBOFのプローブヘッドを備えたBruker AvanceIII HD 300MHzでNMRスペクトルの測定を行った。
[Example 4]
Preparation of 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2-(4-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide
Synthesis of 4,4,4-trifluoro-3-hydroxybutanamide: In a 50 mL round bottom flask was placed ethyl 4,4,4-trifluoro-3-hydroxybutanoate (500 mg, 2.7 mmol, 1 equiv.) in MeOH (5 mL, 4.0 M), NH3 . The resulting solution was stirred at 60° C. for 16 h. The resulting mixture was concentrated. This afforded 500 mg of 4,4,4-trifluoro-3-hydroxybutanamide as a white solid. 1H NMR (300 MHz, DMSO-d 6, ppm) δ 7.62 (ds, 1H), 7.01 (ds, 1H), 3.36-6.34 (m, 1H), 4.27-4.40 (m, 1H), 2.39-2.36 (m, 2H). NMR spectra were recorded on a Bruker AvanceIII HD 300 MHz equipped with a BBOF probehead.
4-アミノ-1,1,1-トリフルオロブタン-2-オールの合成:50mL三つ口丸底フラスコ中へ、4,4,4-トリフルオロ-3-ヒドロキシブタンアミド(500 mg、3.2 mmol、1当量)及びTHF(10 mL)を入れ、LAH(242 mg、6.4 mmol、2.00当量)を氷浴で少しずつ加えた。得られる溶液を室温で16時間撹拌した。この反応が完了した後、0.24 mLの水を加えることにより反応混合物をクエンチし、0.24 mLのNaOH(H20中10%)及び0.72 mLの水を氷浴で逐次的に溶液に加えた。固体をろ過した。得られる混合物を真空下で濃縮した。これにより380 mg(83.43%)の4-アミノ-1,1,1-トリフルオロブタン-2-オールが無色油状物として得られた。1H NMR (300 MHz, CDCL3, ppm) 4.10-4.01 (m, 1H), 2.70-2.66 (m, 2H), 1.51-1.47 (m, 2H).BBOFのプローブヘッドを備えたBruker AvanceIII HD 300MHzでNMRスペクトルの測定を行った。 Synthesis of 4-amino-1,1,1-trifluorobutan-2-ol: In a 50 mL three-neck round-bottom flask, 4,4,4-trifluoro-3-hydroxybutanamide (500 mg, 3.2 mmol, 1 equiv.) and THF (10 mL) were placed, and LAH (242 mg, 6.4 mmol, 2.00 equiv.) was added portionwise in an ice bath. The resulting solution was stirred at room temperature for 16 hours. After the reaction was completed, the reaction mixture was quenched by adding 0.24 mL of water, and 0.24 mL of NaOH (10% in H2O ) and 0.72 mL of water were added successively to the solution in an ice bath. The solid was filtered. The resulting mixture was concentrated under vacuum. This gave 380 mg (83.43%) of 4-amino-1,1,1-trifluorobutan-2-ol as a colorless oil. 1H NMR (300 MHz, CDCL3 , ppm): 4.10-4.01 (m, 1H), 2.70-2.66 (m, 2H), 1.51-1.47 (m, 2H). NMR spectra were measured on a Bruker AvanceIII HD 300 MHz equipped with a BBOF probehead.
4-メチル-N-(4,4,4-トリフルオロ-3-ヒドロキシブチル)ベンゼンスルホンアミドの合成。100mL丸底フラスコ中へ、4-アミノ-1,1,1-トリフルオロブタン-2-オール(350 mg、2.4 mmol、1当量)、TEA(480 mg、4.8 mmol、2.0当量)及びDCM(10 mL)を入れ、TsCl(470 mg、2.4 mmol、1.0当量)を氷浴で加えた。得られる溶液を室温で4時間撹拌した。得られる溶液を50 mLのDCMで希釈した。得られる混合物を2×20 mlの水及び1×20 mLのブラインで洗浄した。混合物を無水硫酸ナトリウム上で乾燥させた。固体をろ過した。得られる混合物を真空下で濃縮した。残渣を、酢酸エチル/石油エーテル(0~50%)を使用してシリカゲルカラムに適用した。これにより600 mg(82.52%)の4-メチル-N-(4,4,4-トリフルオロ-3-ヒドロキシブチル)ベンゼン-1-スルホンアミドが無色油状物として得られた。1H NMR (300 MHz, DMSO-d6, ppm) δ 7.70-7.68 (m, 2H), 7.42-7.40 (m, 2H), 6.23-6.21 (m, 1H), 4.01 -3.96 (m, 1H), 2.87-2.83 (m, 2H), 2.39 (s, 3H), 1.70-1.49 (m, 2H).BBOFのプローブヘッドを備えたBruker AvanceIII HD 300MHzでNMRスペクトルの測定を行った。 Synthesis of 4-methyl-N-(4,4,4-trifluoro-3-hydroxybutyl)benzenesulfonamide. In a 100 mL round bottom flask, 4-amino-1,1,1-trifluorobutan-2-ol (350 mg, 2.4 mmol, 1 equiv), TEA (480 mg, 4.8 mmol, 2.0 equiv) and DCM (10 mL) were added and TsCl (470 mg, 2.4 mmol, 1.0 equiv) was added in ice bath. The resulting solution was stirred at room temperature for 4 hours. The resulting solution was diluted with 50 mL of DCM. The resulting mixture was washed with 2×20 ml of water and 1×20 mL of brine. The mixture was dried over anhydrous sodium sulfate. The solid was filtered. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column using ethyl acetate/petroleum ether (0-50%). This gave 600 mg (82.52%) of 4-methyl-N-(4,4,4-trifluoro-3-hydroxybutyl)benzene-1-sulfonamide as a colorless oil. 1 H NMR (300 MHz, DMSO-d 6, ppm) δ 7.70-7.68 (m, 2H), 7.42-7.40 (m, 2H), 6.23-6.21 (m, 1H), 4.01 -3.96 (m, 1H), 2.87-2.83 (m, 2H), 2.39 (s, 3H), 1.70-1.49 (m, 2H). NMR spectra were recorded on a Bruker AvanceIII HD 300 MHz equipped with a BBOF probehead.
N-(3-(5-ブロモ-1-((2-(トリメチルシリル)エトキシ)メチル)-1H-ピロロ[2,3-b]ピリジン-6-イルオキシ)-4,4,4-トリフルオロブチル)-4-メチルベンゼンスルホンアミドの合成。100mL丸底フラスコ中へ、5-ブロモ-6-フルオロ-1-[[2-(トリメチルシリル)エトキシ]メチル]-1H-ピロロ[2,3-b]ピリジン(300 mg、0.9 mmol、1当量)、4-メチル-N-(4,4,4-トリフルオロ-3-ヒドロキシブチル)ベンゼン-1-スルホンアミド(310 mg、1.0 mmol、1.2当量)、Cs2CO3(566 mg、1.7 mmol、2.0当量)及び1,4-ジオキサン(10 mL)を入れた。得られる溶液を油浴中90℃で16時間撹拌した。反応混合物を冷却した。固体をろ過した。得られる溶液を100 mLのDCMで希釈した。得られる混合物を5×50 mlの水及び1×50 mLのブラインで洗浄した。混合物を無水硫酸ナトリウム上で乾燥させた。固体をろ過した。得られる混合物を真空下で濃縮した。残渣を、酢酸エチル/石油エーテル(0~30%)を使用してシリカゲルカラムに適用した。これにより400 mg(73.95%)のN-[3-[(5-ブロモ-1-[[2-(トリメチルシリル)エトキシ]メチル]-1H-ピロロ[2,3-b]ピリジン-6-イル)オキシ]-4,4,4-トリフルオロブチル]-4-メチルベンゼン-1-スルホンアミドが淡黄色固体として得られた。1H NMR (300 MHz, CDCL3, ppm) 8.17 (bs, 1H), 7.76-7.73 (m, 2H), 7.29-7.27 (m, 3H), 6.51-6.50 (m, 1H), 5.93-5.91 (m, 1H), 5.75-5.72 (m, 2H), 5.63-5.58 (m, 1H), 3.60-3.57 (m, 2H), 3.34-3.32 (m,1H), 3.13-3.11 (m, 1H), 2.46 (s, 3H), 2.31-2.29 (m, 1H), 2.10-2.07 (m, 1H), 1.00-0.85 (m, 2H), 0.01 (s, 9H).BBOFのプローブヘッドを備えたBruker AvanceIII HD 300MHzでNMRスペクトルの測定を行った。 Synthesis of N-(3-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-6-yloxy)-4,4,4-trifluorobutyl)-4-methylbenzenesulfonamide. In a 100 mL round bottom flask was placed 5-bromo-6-fluoro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridine (300 mg, 0.9 mmol, 1 equiv), 4-methyl-N-(4,4,4-trifluoro- 3 -hydroxybutyl)benzene-1-sulfonamide (310 mg, 1.0 mmol, 1.2 equiv), Cs2CO3 (566 mg, 1.7 mmol, 2.0 equiv) and 1,4-dioxane (10 mL). The resulting solution was stirred in an oil bath at 90° C. for 16 h. The reaction mixture was cooled. The solids were filtered. The resulting solution was diluted with 100 mL of DCM. The resulting mixture was washed with 5×50 ml of water and 1×50 mL of brine. The mixture was dried over anhydrous sodium sulfate. The solids were filtered. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column using ethyl acetate/petroleum ether (0-30%). This gave 400 mg (73.95%) of N-[3-[(5-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-6-yl)oxy]-4,4,4-trifluorobutyl]-4-methylbenzene-1-sulfonamide as a pale yellow solid. 1H NMR (300 MHz, CDCL3 , ppm) 8.17 (bs, 1H), 7.76-7.73 (m, 2H), 7.29-7.27 (m, 3H), 6.51-6.50 (m, 1H), 5.93-5.91 (m, 1H), 5.75-5.72 (m, 2H), 5.63-5.58 (m, 1H), 3.60-3.57 (m, 2H), 3.34-3.32 (m,1H), 3.13-3.11 (m, 1H), 2.46 (s, 3H), 2.31-2.29 (m, 1H), 2.10-2.07 (m, 1H), 1.00-0.85 (m, 2H), 0.01 (s, 9H). NMR spectra were measured on a Bruker AvanceIII HD 300 MHz equipped with a BBOF probehead.
1-トシル-4-(トリフルオロメチル)-7-((2-(トリメチルシリル)エトキシ)メチル)-1,3,4,7-テトラヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼパンの合成。窒素の不活性雰囲気でパージされ維持された250mL丸底フラスコ中へ、N-[3-[(5-ブロモ-1-[[2-(トリメチルシリル)エトキシ]メチル]-1H-ピロロ[2,3-b]ピリジン-6-イル)オキシ]-4,4,4-トリフルオロブチル]-4-メチルベンゼン-1-スルホンアミド(700 mg、1.13 mmol、1当量)、CS2CO3(1.1g、3.39 mmol、3.00当量)、CuI(214 mg、1.13 mmol、1.0当量)、2-イソブチリルシクロヘキサン-1-オン(80 mg、0.56 mmol、0.5当量)、DMSO(10 mL)を入れた。得られる溶液を油浴中で120℃で24時間撹拌した。得られる溶液を20 mLの水で希釈した。得られる溶液を2×50 mLの酢酸エチルで抽出した。得られる混合物を1×50 mLのブラインで洗浄した。混合物を無水硫酸ナトリウム上で乾燥させ、真空下で濃縮した。残渣を、酢酸エチル/石油エーテル(0~30%)を使用してシリカゲルカラムに適用した。これにより350 mg(57.38%)の1-トシル-4-(トリフルオロメチル)-7-((2-(トリメチルシリル)エトキシ)メチル)-1,3,4,7-テトラヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピンが淡黄色固体として得られた。1H NMR (300 MHz, CDCL3, ppm) 8.19 (bs, 1H), 7.50-7.47 (m, 2H), 7.39 (s, 1H), 7.24-7.22 (m, 2H), 6.58-6.57 (m, 1H), 5.69-5.66 (m, 1H), 5.55-5.51 (m, 1H), 4.57-4.52 (m, 1H), 3.96-3.94 (m, 1 H), 3.59-3.56 (m,2H), 3.48-3.44 (m, 1H), 2.41 (s, 3H), 2.31-2.29 (m, 1H), 1.95-1.91 (m, 1H), 0.97-0.91 (m, 2H), 0.05 (s, 9H).BBOFのプローブヘッドを備えたBruker AvanceIII HD 300MHzでNMRスペクトルの測定を行った。 Synthesis of 1-tosyl-4-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepane. Into a 250 mL round bottom flask purged and maintained with an inert atmosphere of nitrogen was placed N-[3-[(5-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-6-yl)oxy]-4,4,4-trifluorobutyl]-4-methylbenzene-1- sulfonamide (700 mg, 1.13 mmol, 1 equiv.), CS2CO3 (1.1 g, 3.39 mmol, 3.00 equiv.), CuI (214 mg, 1.13 mmol, 1.0 equiv.), 2-isobutyrylcyclohexan-1-one (80 mg, 0.56 mmol, 0.5 equiv.), and DMSO (10 mL). The resulting solution was stirred in an oil bath at 120° C. for 24 hours. The resulting solution was diluted with 20 mL of water. The resulting solution was extracted with 2×50 mL of ethyl acetate. The resulting mixture was washed with 1×50 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied to a silica gel column using ethyl acetate/petroleum ether (0-30%). This gave 350 mg (57.38%) of 1-tosyl-4-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine as a pale yellow solid. 1H NMR (300 MHz, CDCL3 , ppm) 8.19 (bs, 1H), 7.50-7.47 (m, 2H), 7.39 (s, 1H), 7.24-7.22 (m, 2H), 6.58-6.57 (m, 1H), 5.69-5.66 (m, 1H), 5.55-5.51 (m, 1H), 4.57-4.52 (m, 1H), 3.96-3.94 (m, 1H), 3.59-3.56 (m,2H), 3.48-3.44 (m, 1H), 2.41 (s, 3H), 2.31-2.29 (m, 1H), 1.95-1.91 (m, 1H), 0.97-0.91 (m, 2H), 0.05 (s, 9H). NMR spectra were recorded on a Bruker AvanceIII HD 300 MHz equipped with a BBOF probehead.
4-(トリフルオロメチル)-7-((2-(トリメチルシリル)エトキシ)メチル)-1,3,4,7-テトラヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼパンの合成。250mL三つ口丸底フラスコ中へ、N2下でNa(150 mg、6.5 mmol、1.0当量)、ナフタレン(833 mg、6.5 mmol、10当量)及びDME(3ml)を入れた。Na及びナフタレンが完全に溶解するまで反応混合物を室温で撹拌した。これに、THF(5mL)中の溶液1-トシル-4-(トリフルオロメチル)-7-((2-(トリメチルシリル)エトキシ)メチル)-1,3,4,7-テトラヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン(350 mg、0.65 mmol、1当量)を-78℃で加えた。出発物質がTLCで消費されるまで得られる溶液を-60℃~-40℃で2~3時間撹拌した。次いで5 mLのNH4Clを-10℃で加えることにより反応をクエンチした。得られる溶液を3×10 mLの酢酸エチルで抽出した。混合物を無水硫酸ナトリウム上で乾燥させ、真空下で濃縮した。残渣をシリカゲルカラムに適用し、酢酸エチル/石油エーテル(1/3)で溶出した。これにより220 mg(88%)の4-(トリフルオロメチル)-7-((2-(トリメチルシリル)エトキシ)メチル)-1,3,4,7-テトラヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピンが白色固体として得られた。 Synthesis of 4-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepane. In a 250 mL three-necked round-bottom flask was placed Na (150 mg, 6.5 mmol, 1.0 equiv), naphthalene (833 mg, 6.5 mmol, 10 equiv) and DME (3 ml) under N2 . The reaction mixture was stirred at room temperature until Na and naphthalene were completely dissolved. To this was added a solution of 1-tosyl-4-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine (350 mg, 0.65 mmol, 1 equiv.) in THF (5 mL) at -78°C. The resulting solution was stirred at -60°C to -40°C for 2-3 h until the starting material was consumed by TLC. The reaction was then quenched by adding 5 mL of NH 4 Cl at -10°C. The resulting solution was extracted with 3×10 mL of ethyl acetate. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied to a silica gel column and eluted with ethyl acetate/petroleum ether (1/3). This gave 220 mg (88%) of 4-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine as a white solid.
メチル4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(4-(トリフルオロメチル)-7-((2-(トリメチルシリル)エトキシ)メチル)-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンゾエートの合成。窒素の不活性雰囲気でパージされ維持された100mL丸底フラスコ中へ、メチル2-ブロモ-4-(4-[[2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エン-1-イル]メチル]ピペラジン-1-イル)ベンゾエート(1.2 g、2.28 mmol、4.00当量)、トルエン(20 mL)、4-(トリフルオロメチル)-7-((2-(トリメチルシリル)エトキシ)メチル)-1,3,4,7-テトラヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン(220 mg、0.57 mmol、1当量)、CS2CO3(923 mg、2.84 mmol、5当量)、XantPhos Pd 2G(250 mg、0.46 mmol、0.8当量)を入れた。得られる溶液を110℃で一晩撹拌した。得られる溶液を30 mLの水で希釈した。得られる溶液を2×30 mLの酢酸エチルで抽出した。得られる混合物を1×30 mLのブラインで洗浄した。混合物を無水硫酸ナトリウム上で乾燥させ、真空下で濃縮した。残渣を、酢酸エチル/石油エーテル(0~50%)を使用してシリカゲルカラムに適用した。これにより380 mgの粗製の(80.0%)メチル4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(4-(トリフルオロメチル)-7-((2-(トリメチルシリル)エトキシ)メチル)-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンゾエートが黄色固体として得られた。LC-MS: (ES, m/z): M+H=838, R,T= 3.33分.逆相カラム(C18)により保持時間の測定を行った。Shimadzu LCMS 2020; 50×3.0、Poroshell HPH-C18、2.7ミクロン;溶離液A:水(0.05% NH4HCO3);溶離液B:アセトニトリル;5.0分での5%アセトニトリルから100%アセトニトリルまでの直線的グラジエント;オーブン温度40℃;流量:1.5 mL/分。 Synthesis of methyl 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzoate. Into a 100 mL round bottom flask purged and maintained with an inert atmosphere of nitrogen was placed methyl 2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)benzoate (1.2 g, 2.28 mmol, 4.00 equiv.), toluene (20 mL), 4-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine (220 mg, 0.57 mmol, 1 equiv.), CS2CO3 ( 923 mg, 2.84 mmol, 5 equiv.), and XantPhos Pd 2G (250 mg, 0.46 mmol, 0.8 equiv.). The resulting solution was stirred at 110° C. overnight. The resulting solution was diluted with 30 mL of water. The resulting solution was extracted with 2×30 mL of ethyl acetate. The resulting mixture was washed with 1×30 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied to a silica gel column using ethyl acetate/petroleum ether (0-50%). This gave 380 mg of crude (80.0%) methyl 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzoate as a yellow solid. LC-MS: (ES, m/z): M+H=838, R,T= 3.33 min. Retention time was measured on a reversed phase column (C18). Shimadzu LCMS 2020; 50×3.0, Poroshell HPH-C18, 2.7 micron; Eluent A: water (0.05% NH 4 HCO 3 ); Eluent B: acetonitrile; Linear gradient from 5% acetonitrile to 100% acetonitrile in 5.0 min; Oven temperature 40° C.; Flow rate: 1.5 mL/min.
メチル4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(4-(トリフルオロメチル)-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンゾエートの合成。40mLバイアル中へ、メチル4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(4-(トリフルオロメチル)-7-((2-(トリメチルシリル)エトキシ)メチル)-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンゾエート(380 mg、0.45 mmol、1当量)、THF(20 mL)、TBAF.3H2O(708 mg、2.25 mmol、5当量)、エタン-1,2-ジアミン(540 mg、9.0 mmol、20当量)を入れた。得られる溶液を油浴中で70℃で一晩撹拌した。得られる溶液を20 mLの水で希釈した。得られる溶液を3×30 mLの酢酸エチルで抽出した。得られる混合物を2×20 mLのブラインで洗浄した。混合物を無水硫酸ナトリウム上で乾燥させ、真空下で濃縮した。残渣を、酢酸エチル/石油エーテル(0~50%)を使用してシリカゲルカラムに適用した。これにより300 mg(93%)のメチル4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(4-(トリフルオロメチル)-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンゾエートが淡黄色固体として得られた。1H NMR (300 MHz, CDCL3, ppm) 10.78 (bs, 1H), 7.75-7.72 (m, 1H), 7.29-7.24 (m, 3H), 7.00-6.97 (m, 2H), 6.59-6.56 (m, 2H), 6.28-6.26 (m, 1H), 5.28-5.20 (m, 1H), 3.98-3.96 (m, 1H), 3.79-3.77 (m, 1H), 3.59 (s, 1H), 3.24-3.23 (m, 3H), 2.84 (m, 2H), 2.31-2.28 (m, 4H), 2.26-2.24 (m, 4H), 1.49-1.47 (m, 2H), 1.34-1.24 (m, 4H), 1.00 (s, 6H), 0.96-0.90 (m, 2H). Synthesis of methyl 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzoate. Into a 40 mL vial was placed methyl 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzoate (380 mg, 0.45 mmol, 1 equiv.), THF (20 mL), TBAF.3H2O (708 mg, 2.25 mmol, 5 equiv.), and ethane-1,2-diamine (540 mg, 9.0 mmol, 20 equiv.). The resulting solution was stirred overnight at 70°C in an oil bath. The resulting solution was diluted with 20 mL of water. The resulting solution was extracted with 3×30 mL of ethyl acetate. The resulting mixture was washed with 2×20 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied to a silica gel column using ethyl acetate/petroleum ether (0-50%). This afforded 300 mg (93%) of methyl 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzoate as a pale yellow solid. 1H NMR (300 MHz, CDCL3 , ppm) 10.78 (bs, 1H), 7.75-7.72 (m, 1H), 7.29-7.24 (m, 3H), 7.00-6.97 (m, 2H), 6.59-6.56 (m, 2H), 6.28-6.26 (m, 1H), 5.28-5.20 (m, 1H), 3.98-3.96 (m, 1H), 3.79-3.77 (m, 1H), 3.59 (s, 1H), 3.24-3.23 (m, 3H), 2.84 (m, 2H), 2.31-2.28 (m, 4H), 2.26-2.24 (m, 4H), 1.49-1.47 (m, 2H), 1.34-1.24 (m, 4H), 1.00 (s, 6H), 0.96-0.90 (m, 2H).
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(4-(トリフルオロメチル)-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)安息香酸の合成。40mLバイアル中へ、メチル4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(4-(トリフルオロメチル)-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンゾエート(200 mg、0.28 mmol、1当量)、MeOH(6 mL)、1,4-ジオキサン(6 mL)、H2O(2 mL)、NaOH(67 mg、1.68 mmol、6.00当量)を入れた。得られる溶液を油浴中で60℃で一晩撹拌した。得られる混合物を真空下で濃縮した。HCl(2モル/L)で溶液のpH値を5~6に調整した。得られる溶液を2×50 mLのジクロロメタン/MeOH(v:v=10:l)で抽出した。得られる混合物を2×200 mLのブラインで洗浄した。混合物を無水硫酸ナトリウム上で乾燥させ、真空下で濃縮した。これにより157 mg(81.0%)の4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1、l'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(4-(トリフルオロメチル)-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)安息香酸が淡黄色固体として得られた。LC-MS: (ES, m/z): M+H=694, R,T= 2.43分.逆相カラム(C18)により保持時間の測定を行った。Shimadzu LCMS 2020; 50×3.0、Poroshell HPH-C18、2.7ミクロン;溶離液A:水(0.05% NH4HCO3);溶離液B:アセトニトリル;5.0分で5%アセトニトリルから100%アセトニトリルまでの直線的グラジエント;オーブン温度40℃;流量:1.5 mL/分。 Synthesis of 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzoic acid. In a 40 mL vial, methyl 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzoate (200 mg, 0.28 mmol, 1 equiv.), MeOH (6 mL), 1,4-dioxane (6 mL), H2O (2 mL), NaOH (67 mg, 1.68 mmol, 6.00 equiv.) were added. The resulting solution was stirred overnight at 60°C in an oil bath. The resulting mixture was concentrated under vacuum. The pH value of the solution was adjusted to 5-6 with HCl (2 mol/L). The resulting solution was extracted with 2×50 mL of dichloromethane/MeOH (v:v=10:l). The resulting mixture was washed with 2×200 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This gave 157 mg (81.0%) of 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzoic acid as a pale yellow solid. LC-MS: (ES, m/z): M+H=694, R,T= 2.43 min. Retention time was measured using a reverse phase column (C18). Shimadzu LCMS 2020; 50×3.0, Poroshell HPH-C18, 2.7 micron; Eluent A: water (0.05% NH 4 HCO 3 ); Eluent B: acetonitrile; linear gradient from 5% acetonitrile to 100% acetonitrile in 5.0 min; oven temperature 40 °C; flow rate: 1.5 mL/min.
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)-2-(4-(トリフルオロメチル)-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミドの合成。40mL丸底フラスコ中へ、4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(4-(トリフルオロメチル)-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)安息香酸(57 mg、0.08 mmol、1当量)、DCM(3mL)、3-ニトロ-4-[[(オキサン-4-イル)メチル]アミノ]ベンゼン-1-スルホンアミド(25.2 mg、0.08 mmol、1.00当量)、EDCI(30.6 mg、0.16 mmol、2当量)、DMAP(39.0 mg、0.32 mmol、4当量)を入れた。得られる溶液を25度で一晩撹拌した。得られる混合物を真空下で濃縮した。残渣を、ジクロロメタン/メタノール(10:1)を使用してシリカゲルカラムに適用した。粗生成物をFlash-Prep-HPLCにより以下の条件で精製した(IntelFlash-1):カラム、C18逆相カラム;移動相、水(10MMOL/LNH4HCO3+0.05%NH3.H2O)及びCH3CN(20.0%CH3CNを30分で90.0%まで上昇させる);検出器、UV 220 nm。これにより32 mg(40.0%)の4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1、l'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)-2-(4-(トリフルオロメチル)-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミドが黄色固体として得られた。LC-MS: (ES, m/z): M+1=991, R,T= 2.41分.逆相カラム(C18)により保持時間の測定を行った。Shimadzu LCMS 2020; 50×3.0 Agilent Poroshell HPH-C18、2.7 um;溶離液A:水(0.05%アンモニア水);溶離液B:アセトニトリル;7.0分で5%アセトニトリルから95%アセトニトリルまでの直線的グラジエント;オーブン温度40℃;流量:1.5 mL/分。1H NMR (300 MHz, CDCL3, ppm) δ 11.43 (ds, 1H), 9.99 (ds, 1H), 8.72 (s, 1H), 8.40 (ds, 1H), 7.93-7.85 (m, 2H), 7.37-7.35 (m, 2H), 7.26 (s, 1H), 7.02-6.93 (m, 3H), 6.71-6..64 (m, 3H), 6.27 (s, 1H), 4.58 (s, 1H), 4.05-3.15 (m, 23H), 2.70-2.35 (m, 7H), 2.03 (s, 3H), 1.92-1.90 (m, 1H), 1.89-1.87 (m, 2H), 1.71-1.67 (m, 2H), 1.53-1.45 (m, 3H), 1.00 (s, 6H).BBOFのプローブヘッドを備えたBruker AvanceIII HD 300MHzでNMRスペクトルの測定を行った。 Synthesis of 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2-(4-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide. Into a 40 mL round bottom flask was placed 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzoic acid (57 mg, 0.08 mmol, 1 equiv.), DCM (3 mL), 3-nitro-4-[[(oxan-4-yl)methyl]amino]benzene-1-sulfonamide (25.2 mg, 0.08 mmol, 1.00 equiv.), EDCI (30.6 mg, 0.16 mmol, 2 equiv.), and DMAP (39.0 mg, 0.32 mmol, 4 equiv.). The resulting solution was stirred at 25° overnight. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column using dichloromethane/methanol (10:1). The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): column, C18 reverse phase column; mobile phase, water ( 10MMOL / LNH4HCO3 +0.05% NH3.H2O ) and CH3CN (20.0% CH3CN increased to 90.0% in 30 min); detector, UV 220 nm. This gave 32 mg (40.0%) of 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2-(4-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide as a yellow solid. LC-MS: (ES, m/z): M+1=991, R,T= 2.41 min. Retention time was measured using a reverse phase column (C18). Shimadzu LCMS 2020; 50×3.0 Agilent Poroshell HPH-C18, 2.7 um; Eluent A: water (0.05% aqueous ammonia); Eluent B: acetonitrile; linear gradient from 5% acetonitrile to 95% acetonitrile in 7.0 min; oven temperature 40 °C; flow rate: 1.5 mL/min. 1H NMR (300 MHz, CDCL3 , ppm) δ 11.43 (ds, 1H), 9.99 (ds, 1H), 8.72 (s, 1H), 8.40 (ds, 1H), 7.93-7.85 (m, 2H), 7.37-7.35 (m, 2H), 7.26 (s, 1H), 7.02-6.93 (m, 3H), 6.71-6..64 (m, 3H), 6.27 (s, 1H), 4.58 (s, 1H), 4.05-3.15 (m, 23H), 2.70-2.35 (m, 7H), 2.03 (s, 3H), 1.92-1.90 (m, 1H), 1.89-1.87 (m, 2H), 1.71-1.67 (m, 2H), 1.53-1.45 (m, 3H), 1.00 (s, 6H). NMR spectra were recorded on a Bruker AvanceIII HD 300 MHz equipped with a BBOF probehead.
[実施例5]
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]チアゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミドの調製
メチル3-[(5-ブロモ-1-[[2-(トリメチルシリル)エトキシ]メチル]-1H-ピロロ[2,3-b]ピリジン-6-イル)スルファニル]プロパノエートの合成。40mL丸底フラスコ中へ、5-ブロモ-6-フルオロ-1-[[2-(トリメチルシリル)エトキシ]メチル]-1H-ピロロ[2,3-b]ピリジン(3 g、8.7 mmol、1当量)、メチル3-スルファニルプロパノエート(2.1 g、17.4 mmol、2.0当量)、ACN(30 mL)、Cs2CO3(7.1 g、21.7 mmol、2.5当量)を入れた。得られる溶液を70℃で1時間撹拌した。固体をろ過した。得られる混合物を濃縮した。残渣を酢酸エチル/石油エーテル(0~10%)を使用してシリカゲルカラムに適用した。これにより300 mg(7.75%)のメチル3-[(5-ブロモ-1-[[2-(トリメチルシリル)エトキシ]メチル]-1H-ピロロ[2,3-b]ピリジン-6-イル)スルファニル]プロパノエートが無色油状物として得られた。LC-MS: (ES, m/z): M+1=445/447, R,T= 1.47 分.逆相カラム(C18)により保持時間の測定を行った。Shimadzu LCMS 2020; 50×3.0 Kinetex 2.6u XB-C18、2.6ミクロン;溶離液A:水(0.05% TFA);溶離液B:アセトニトリル;直線的グラジエント。
[Example 5]
Preparation of 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]thiazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide. Synthesis of methyl 3-[(5-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-6-yl)sulfanyl]propanoate. Into a 40 mL round bottom flask was placed 5-bromo-6-fluoro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridine (3 g, 8.7 mmol, 1 equiv.), methyl 3 -sulfanylpropanoate (2.1 g, 17.4 mmol, 2.0 equiv.), ACN (30 mL), and Cs2CO3 (7.1 g, 21.7 mmol, 2.5 equiv.). The resulting solution was stirred at 70°C for 1 h. The solids were filtered. The resulting mixture was concentrated. The residue was applied to a silica gel column with ethyl acetate/petroleum ether (0-10%). This gave 300 mg (7.75%) of methyl 3-[(5-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-6-yl)sulfanyl]propanoate as a colorless oil. LC-MS: (ES, m/z): M+1=445/447, R,T= 1.47 min. Retention times were determined using a reversed phase column (C18). Shimadzu LCMS 2020; 50×3.0 Kinetex 2.6u XB-C18, 2.6 microns; Eluent A: water (0.05% TFA); Eluent B: acetonitrile; linear gradient.
3-[(5-ブロモ-1-[[2-(トリメチルシリル)エトキシ]メチル]-1H-ピロロ[2,3-b]ピリジン-6-イル)スルファニル]プロパン-1-オールの合成。窒素の不活性雰囲気でパージされ維持された8mL丸底フラスコ中へ、メチル3-[(5-ブロモ-1-[[2-(トリメチルシリル)エトキシ]メチル]-1H-ピロロ[2,3-b]ピリジン-6-イル)スルファニル]プロパノエート(300 mg、0.67 mmol、1当量)及びTHF(10 mL)を入れた。これに続いてLiAlH4(51 mg、1.3 mmol、2.00当量)を-78℃で慎重に加えた。得られる溶液を室温で1時間撹拌した。この反応が完了した後、0.5 mLの水を加えることにより反応混合物をクエンチし、0.5 mLのNaOH(H2O中10%)及び1.5 mLの水を氷浴で溶液に逐次的に加えた。固体をろ過した。得られる混合物を真空下で濃縮した。これにより200 mg(71.14%)の3-[(5-ブロモ-1-[[2-(トリメチルシリル)エトキシ]メチル]-1H-ピロロ[2,3-b]ピリジン-6-イル)スルファニル]プロパン-1-オールが黄色油状物として得られた。H-NMR: (CDCl3, 300ppm): 7.99(s, 1H), 7.24-7.20(m, 1H), 6.49-6.41(m, 1H), 5.32(s, 2H), 3.84-3.78(m, 2H), 3.58-3.50(m, 2H), 3.46-3.40(m, 2H), 2.09-2.01(m, 2H), 0.96-0.88(m, 2H), 0.05(s, 9H). Synthesis of 3-[(5-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-6-yl)sulfanyl]propan-1-ol. Into an 8 mL round bottom flask purged and maintained with an inert atmosphere of nitrogen was placed methyl 3-[(5-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-6-yl)sulfanyl]propanoate (300 mg, 0.67 mmol, 1 equiv.) and THF (10 mL). This was followed by careful addition of LiAlH4 (51 mg, 1.3 mmol, 2.00 equiv.) at -78°C. The resulting solution was stirred at room temperature for 1 h. After the reaction was completed, the reaction mixture was quenched by adding 0.5 mL of water, and 0.5 mL of NaOH (10% in H2O ) and 1.5 mL of water were added sequentially to the solution in an ice bath. The solid was filtered. The resulting mixture was concentrated under vacuum. This gave 200 mg (71.14%) of 3-[(5-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-6-yl)sulfanyl]propan-1-ol as a yellow oil. H-NMR: (CDCl3, 300ppm): 7.99(s, 1H), 7.24-7.20(m, 1H), 6.49-6.41(m, 1H), 5.32(s, 2H), 3.84-3.78(m, 2H), 3.58-3.50(m, 2H), 3.46-3.40(m, 2H), 2.09-2.01(m, 2H), 0.96-0.88(m, 2H), 0.05(s, 9H).
N-[6-[(3-ヒドロキシプロピル)スルファニル]-1-[[2-(トリメチルシリル)エトキシ]メチル]-1H-ピロロ[2,3-b]ピリジン-5-イル]-4-メチルベンゼン-1-スルホンアミドの合成。窒素の不活性雰囲気でパージされ維持された100mL丸底フラスコ中へ、4-メチルベンゼン-1-スルホンアミド(1.6 g、9.6 mmol、2当量)、3-[(5-ブロモ-1-[[2-(トリメチルシリル)エトキシ]メチル]-1H-ピロロ[2,3-b]ピリジン-6-イル)スルファニル]プロパン-1-オール(2 g、4.8 mmol、1当量)、1、10-フェナントロリン(0.17 g、0.94 mmol、0.20当量)、CuI(0.18 g、0.96 mmol、0.2当量)、Cs2CO3(3.1 g、9.6 mmol、2当量)をDMSO(30 mL)下で入れた。得られる溶液を120℃で72時間撹拌した。得られる溶液を30 mLのH20で希釈した。固体をろ過した。得られる溶液を3×50 mLの酢酸エチルで抽出した。混合物を無水硫酸ナトリウム上で乾燥させ、真空下で濃縮した。残渣を、酢酸エチル/石油エーテル(0:1~1:1)を使用してシリカゲルカラムに適用した。これにより1.0 g(41.11%)のN-[6-[(3-ヒドロキシプロピル)スルファニル]-1-[[2-(トリメチルシリル)エトキシ]メチル]-1H-ピロロ[2,3-b]ピリジン-5-イル]-4-メチルベンゼン-1-スルホンアミドが白色固体として得られた。LC-MS: (ES, m/z): M+1=508, R,T= 2.845 分.逆相カラム(C18)により保持時間の測定を行った。Shimadzu LCMS 2020; 50×3.0 Kinetex 2.6u XB-C18、2.6ミクロン;溶離液A:水(0.05% TFA);溶離液B:アセトニトリル;直線的グラジエント。 Synthesis of N-[6-[(3-hydroxypropyl)sulfanyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-4-methylbenzene-1-sulfonamide. Into a 100 mL round bottom flask purged and maintained with an inert atmosphere of nitrogen, 4-methylbenzene-1-sulfonamide (1.6 g, 9.6 mmol, 2 equiv.), 3-[(5-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-6-yl)sulfanyl]propan-1 - ol (2 g, 4.8 mmol, 1 equiv.), 1,10-phenanthroline (0.17 g, 0.94 mmol, 0.20 equiv.), CuI (0.18 g, 0.96 mmol, 0.2 equiv.), Cs2CO3 (3.1 g, 9.6 mmol, 2 equiv.) were added under DMSO (30 mL). The resulting solution was stirred at 120° C. for 72 h. The resulting solution was diluted with 30 mL of H20 . The solid was filtered. The resulting solution was extracted with 3×50 mL of ethyl acetate. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate/petroleum ether (0:1 to 1:1). This gave 1.0 g (41.11%) of N-[6-[(3-hydroxypropyl)sulfanyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-4-methylbenzene-1-sulfonamide as a white solid. LC-MS: (ES, m/z): M+1=508, R,T= 2.845 min. Retention times were determined using a reversed phase column (C18). Shimadzu LCMS 2020; 50×3.0 Kinetex 2.6u XB-C18, 2.6 microns; Eluent A: water (0.05% TFA); Eluent B: acetonitrile; linear gradient.
10-(4-メチルベンゼンスルホニル)-4-[[2-(トリメチルシリル)エトキシ]メチル]-14-チア-2,4,10-トリアザトリシクロ[7.5.0.0^[3,7]]テトラデカ-1(9),2,5,7-テトラエンの合成。8mL丸底フラスコ中へ、N-[6-[(3-ヒドロキシプロピル)スルファニル]-1-[[2-(トリメチルシリル)エトキシ]メチル]-1H-ピロロ[2,3-b]ピリジン-5-イル]-4-メチルベンゼン-1-スルホンアミド(240 mg、0.47 mmol、1当量)、THF(5ml)、PPh3(248 mg、0.95 mmol、2当量)を入れた。これに続いて0℃で撹拌しながら、DEAD(164 mg、0.95 mmol、2.00当量)を滴下して加えた。得られる溶液を室温で12時間撹拌した。得られる混合物を濃縮した。残渣を、酢酸エチル/石油エーテル(0:1~1:2)を使用してシリカゲルカラムに適用した。これにより200 mg(86.40%)の10-(4-メチルベンゼンスルホニル)-4-[[2-(トリメチルシリル)エトキシ]メチル]-14-チア-2,4,10-トリアザトリシクロ[7.5.0.0^[3,7]]テトラデカ-1(9),2,5,7-テトラエンが無色固体として得られた。H-NMR:(CDCl3, 300ppm): 7.82(s, 1H),7.69-7.58(m, 3H),7.38-7.36(d, J=6Hz, 2H), 6.55-6.54(d, J=3Hz, 2H), 5.55(s, 2H),4.30-4.23(m, 2H)4.06-4.02(m, 2H), 3.57-3.49(m, 2H), 2.77(s, 2H), 2.50(s, 3H),2.07-1.99(m, 3H),1.24-1.04(m, 9H), 0.87-0.84(m, 3H), 0.02(s, 9H). Synthesis of 10-(4-methylbenzenesulfonyl)-4-[[2-(trimethylsilyl)ethoxy]methyl]-14-thia-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradeca-1(9),2,5,7-tetraene. In an 8 mL round bottom flask was placed N-[6-[(3-hydroxypropyl)sulfanyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-4-methylbenzene-1-sulfonamide (240 mg, 0.47 mmol, 1 equiv), THF (5 ml), and PPh3 (248 mg, 0.95 mmol, 2 equiv). This was followed by the dropwise addition of DEAD (164 mg, 0.95 mmol, 2.00 equiv) with stirring at 0°C. The resulting solution was stirred at room temperature for 12 h. The resulting mixture was concentrated. The residue was applied to a silica gel column with ethyl acetate/petroleum ether (0:1-1:2). This gave 200 mg (86.40%) of 10-(4-methylbenzenesulfonyl)-4-[[2-(trimethylsilyl)ethoxy]methyl]-14-thia-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradeca-1(9),2,5,7-tetraene as a colorless solid. H-NMR: (CDCl3, 300ppm): 7.82(s, 1H), 7.69-7.58(m, 3H), 7.38-7.36(d, J=6Hz, 2H), 6.55-6.54(d, J=3Hz, 2H), 5.55(s, 2H), 4.30-4.23(m, 2H), 4.06-4.02(m, 2H), 3.57-3.49(m, 2H), 2.77(s, 2H), 2.50(s, 3H), 2.07-1.99(m, 3H), 1.24-1.04(m, 9H), 0.87-0.84(m, 3H), 0.02(s, 9H).
4-[[2-(トリメチルシリル)エトキシ]メチル]-14-チア-2,4,10-トリアザトリシクロ[7.5.0.0^[3,7]]テトラデカ-1(9),2,5,7-テトラエンの合成。8mL丸底フラスコ中へ、ナフタレン(314 mg、2.4 mmol、6当量)、Na(90 mg、3.9 mmol、9.6当量)及びDME(5mL)を入れた。得られる溶液を室温で0.5時間撹拌した。得られる溶液を10-(4-メチルベンゼンスルホニル)-4-[[2-(トリメチルシリル)エトキシ]メチル]-14-チア-2,4,10-トリアザトリシクロ[7.5.0.0^[3,7]]テトラデカ-1(9),2,5,7-テトラエン(200 mg、0.41 mmol、1当量)、THF(10 mL)の40mL丸底フラスコに加えた。得られる溶液を室温で3時間撹拌した。次いで1 mLのNH4Clを加えることにより反応をクエンチした。得られる混合物を濃縮した。残渣を、酢酸エチル/石油エーテル(0~50%)を使用してシリカゲルカラムに適用した。これにより120 mg(87.57%)の4-[[2-(トリメチルシリル)エトキシ]メチル]-14-チア-2,4,10-トリアザトリシクロ[7.5.0.0^[3,7]]テトラデカ-1(9),2,5,7-テトラエンが黄色固体として得られた。LC-MS:(ES, m/z): M+1=649, R,T= 0.80 分.逆相カラム(C18)により保持時間の測定を行った。Shimadzu LCMS 2020; 50×3.0 Kinetex 2.6u XB-C18、2.6ミクロン;溶離液A:水(0.05% TFA);溶離液B:アセトニトリル;直線的グラジエント。 Synthesis of 4-[[2-(trimethylsilyl)ethoxy]methyl]-14-thia-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradeca-1(9),2,5,7-tetraene. In an 8 mL round bottom flask was placed naphthalene (314 mg, 2.4 mmol, 6 equiv), Na (90 mg, 3.9 mmol, 9.6 equiv) and DME (5 mL). The resulting solution was stirred at room temperature for 0.5 h. The resulting solution was added to a 40 mL round bottom flask containing 10-(4-methylbenzenesulfonyl)-4-[[2-(trimethylsilyl)ethoxy]methyl]-14-thia-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradeca-1(9),2,5,7-tetraene (200 mg, 0.41 mmol, 1 equiv), THF (10 mL). The resulting solution was stirred at room temperature for 3 hours. The reaction was then quenched by adding 1 mL of NH 4 Cl. The resulting mixture was concentrated. The residue was applied to a silica gel column with ethyl acetate/petroleum ether (0-50%). This gave 120 mg (87.57%) of 4-[[2-(trimethylsilyl)ethoxy]methyl]-14-thia-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradeca-1(9),2,5,7-tetraene as a yellow solid. LC-MS: (ES, m/z): M+1=649, R,T= 0.80 min. Retention times were determined using a reversed phase column (C18). Shimadzu LCMS 2020; 50×3.0 Kinetex 2.6u XB-C18, 2.6 microns; Eluent A: water (0.05% TFA); Eluent B: acetonitrile; linear gradient.
メチル4-(4-[[2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エン-1-イル]メチル]ピペラジン-1-イル)-2-(4-[[2-(トリメチルシリル)エトキシ]メチル]-14-チア-2,4,10-トリアザトリシクロ[7.5.0.0^[3,7]]テトラデカ-1(9),2,5,7-テトラエン-10-イル)ベンゾエートの合成。窒素の不活性雰囲気でパージされ維持された8mL丸底フラスコ中へ、4-[[2-(トリメチルシリル)エトキシ]メチル]-14-チア-2,4,10-トリアザトリシクロ[7.5.0.0^[3,7]]テトラデカ-1(9),2,5,7-テトラエン(120 mg、0.36 mmol、1当量)、メチル2-ブロモ-4-(4-[[2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エン-1-イル]メチル]ピペラジン-1-イル)ベンゾエート(380 mg、0.71 mmol、2.00当量)、カエシオ(caesio)メタンペルオキソエートセシウム(233 mg、0.71 mmol、2.00当量)、トルエン(3 mL)、XantPhos Pd(34 mg、0.04 mmol、0.1当量)を入れた。得られる溶液を110℃で一晩撹拌した。得られる混合物を濃縮した。残渣を、酢酸エチル/石油エーテル(0~50%)を使用してシリカゲルカラムに適用した。これにより、150 mg(53.32%)のメチル4-(4-[[2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エン-1-イル]メチル]ピペラジン-1-イル)-2-(4-[[2-(トリメチルシリル)エトキシ]メチル]-14-チア-2,4,10-トリアザトリシクロ[7.5.0.0^[3,7]]テトラデカ-1(9),2,5,7-テトラエン-10-イル)ベンゾエートが黄色固体として得られた。LC-MS: (ES, m/z): M+1=786, R,T= 1.26 分.逆相カラム(C18)により保持時間の測定を行った。Shimadzu LCMS 2020; 50×3.0 Kinetex 2.6u XB-C18、2.6ミクロン;溶離液A:水(0.05% TFA);溶離液B:アセトニトリル;直線的グラジエント。H-NMR:(CDCl3, 300ppm):7.64-7.61(d,J=9Hz, 1H), 7.35(s, 1H), 7.28-7.26(m, 2H), 7.19-7.18(m, 1H), 6.99-6.97(m, 2H), 6.52-6.47(m, 2H), 6.27-6.26(d, J=3Hz, 1H), 5.61(s, 2H), 3.96-3.84(m, 2H), 3.60-3.54(m, 5H), 3.28-3.16(m, 6H), 2.82(s, 2H), 2.33-2.24(m, 6H), 2.06-2.02(m, 4H), 1.49-1.45(m, 2H), 1.28-1.19(m, 4H), 1.03-0.88(m, 6H), 0.00(s, 9H). Synthesis of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-(4-[[2-(trimethylsilyl)ethoxy]methyl]-14-thia-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradec-1(9),2,5,7-tetraen-10-yl)benzoate. Into an 8 mL round bottom flask purged and maintained with an inert atmosphere of nitrogen was placed 4-[[2-(trimethylsilyl)ethoxy]methyl]-14-thia-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradec-1(9),2,5,7-tetraene (120 mg, 0.36 mmol, 1 equiv.), methyl 2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)benzoate (380 mg, 0.71 mmol, 2.00 equiv.), caesiomethaneperoxoate cesium (233 mg, 0.71 mmol, 2.00 equiv.), toluene (3 mL), and XantPhos Pd (34 mg, 0.04 mmol, 0.1 equiv.). The resulting solution was stirred at 110° C. overnight. The resulting mixture was concentrated. The residue was applied to a silica gel column with ethyl acetate/petroleum ether (0-50%). This gave 150 mg (53.32%) of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-(4-[[2-(trimethylsilyl)ethoxy]methyl]-14-thia-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradec-1(9),2,5,7-tetraen-10-yl)benzoate as a yellow solid. LC-MS: (ES, m/z): M+1=786, R,T= 1.26 min. Retention time was measured by reversed phase column (C18). Shimadzu LCMS 2020; 50×3.0 Kinetex 2.6u XB-C18, 2.6 micron; Eluent A: water (0.05% TFA); Eluent B: acetonitrile; linear gradient. H-NMR: (CDCl3, 300ppm): 7.64-7.61(d,J=9Hz, 1H), 7.35(s, 1H), 7.28-7.26(m, 2H), 7.19-7.18(m, 1H), 6.99-6.97(m, 2H), 6.52-6.47(m, 2H), 6.27-6.26(d, J=3Hz, 1H), 5.61(s, 2H), 3.96-3.84(m, 2H), 3.60-3.54(m, 5H), 3.28-3.16(m, 6H), 2.82(s, 2H), 2.33-2.24(m, 6H), 2.06-2.02(m, 4H), 1.49-1.45(m, 2H), 1.28-1.19(m, 4H), 1.03-0.88(m, 6H), 0.00(s, 9H).
メチル4-(4-[[2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エン-1-イル]メチル]ピペラジン-1-イル)-2-[14-チア-2,4,10-トリアザトリシクロ[7.5.0.0^[3,7]]テトラデカ-1(9),2,5,7-テトラエン-10-イル]ベンゾエートの合成。8-mL丸底フラスコ中へ、メチル4-(4-[[2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エン-1-イル]メチル]ピペラジン-1-イル)-2-(4-[[2-(トリメチルシリル)エトキシ]メチル]-14-チア-2,4,10-トリアザトリシクロ[7.5.0.0^[3,7]]テトラデカ-1(9),2,5,7-テトラエン-10-イル)ベンゾエート(150 mg、0.19 mmol、1当量)、エタン-1,2-ジアミン(229 mg、3.8 mmol、20当量)、TBAF(997 mg、3.8 mmol、20当量)、THF(10 mL)を入れた。得られる溶液を70℃で14時間撹拌した。得られる混合物を濃縮した。残渣を、酢酸エチル/石油エーテル(0~50%)を使用してシリカゲルカラムに適用した。これにより、50 mg(39.95%)のメチル4-(4-[[2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エン-1-イル]メチル]ピペラジン-1-イル)-2-[14-チア-2,4,10-トリアザトリシクロ[7.5.0.0^[3,7]]テトラデカ-1(9),2,5,7-テトラエン-10-イル]ベンゾエートが黄色固体として得られた。LC-MS: (ES, m/z): M+1=656, R,T= 1.05 分.逆相カラム(C18)により保持時間の測定を行った。Shimadzu LCMS 2020; 50×3.0 Kinetex 2.6u XB-C18、2.6ミクロン;溶離液A:水(0.05% TFA);溶離液B:アセトニトリル;直線的グラジエント。 Synthesis of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[14-thia-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradec-1(9),2,5,7-tetraen-10-yl]benzoate. Into an 8-mL round-bottom flask was placed methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-(4-[[2-(trimethylsilyl)ethoxy]methyl]-14-thia-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradec-1(9),2,5,7-tetraen-10-yl)benzoate (150 mg, 0.19 mmol, 1 equiv.), ethane-1,2-diamine (229 mg, 3.8 mmol, 20 equiv.), TBAF (997 mg, 3.8 mmol, 20 equiv.), and THF (10 mL). The resulting solution was stirred at 70° C. for 14 h. The resulting mixture was concentrated. The residue was applied to a silica gel column using ethyl acetate/petroleum ether (0-50%). This gave 50 mg (39.95%) of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[14-thia-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradec-1(9),2,5,7-tetraen-10-yl]benzoate as a yellow solid. LC-MS: (ES, m/z): M+1=656, R,T= 1.05 min. Retention time was measured on a reversed phase column (C18). Shimadzu LCMS 2020; 50×3.0 Kinetex 2.6u XB-C18, 2.6 microns; Eluent A: water (0.05% TFA); Eluent B: acetonitrile; linear gradient.
4-(4-[[2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エン-1-イル]メチル]ピペラジン-1-イル)-2-[14-チア-2,4,10-トリアザトリシクロ[7.5.0.0^[3,7]]テトラデカ-1(9),2,5,7-テトラエン-10-イル]安息香酸の合成。8-mL丸底フラスコ中へ、メチル4-(4-[[2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エン-1-イル]メチル]ピペラジン-1-イル)-2-[14-チア-2,4,10-トリアザトリシクロ[7.5.0.0^[3,7]]テトラデカ-1(9),2,5,7-テトラエン-10-イル]ベンゾエート(65 mg、0.10 mmol、1当量)、1,4-ジオキサン(1 mL)、H20(1 mL)、NaOH(23.95 mg、0.60 mmol、6.00当量)を入れた。得られる溶液を90℃で14時間撹拌した。HCl(2モル/L)で溶液のpH値を5に調整した。得られる混合物を濃縮した。残渣を、ジクロロメタン/メタノール(0~10%)を使用してシリカゲルカラムに適用した。これにより30 mg(46.80%)の4-(4-[[2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エン-1-イル]メチル]ピペラジン-1-イル)-2-[14-チア-2,4,10-トリアザトリシクロ[7.5.0.0^[3,7]]テトラデカ-1(9),2,5,7-テトラエン-10-イル]安息香酸が黄色固体として得られた。 Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[14-thia-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradec-1(9),2,5,7-tetraen-10-yl]benzoic acid. In an 8-mL round-bottom flask, methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[14-thia-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradec-1(9),2,5,7-tetraen-10-yl]benzoate (65 mg, 0.10 mmol, 1 equiv.), 1,4-dioxane (1 mL), H2O (1 mL), and NaOH (23.95 mg, 0.60 mmol, 6.00 equiv.) were added. The resulting solution was stirred at 90°C for 14 h. The pH value of the solution was adjusted to 5 with HCl (2 mol/L). The resulting mixture was concentrated. The residue was applied to a silica gel column using dichloromethane/methanol (0-10%). This gave 30 mg (46.80%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[14-thia-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradec-1(9),2,5,7-tetraen-10-yl]benzoic acid as a yellow solid.
4-(4-[[2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エン-1-イル]メチル]ピペラジン-1-イル)-N-(3-ニトロ-4-[[(オキサン-4-イル)メチル]アミノ]ベンゼンスルホニル)-2-[14-チア-2,4,10-トリアザトリシクロ[7.5.0.0^[3,7]]テトラデカ-1(9),2,5,7-テトラエン-10-イル]ベンズアミドの合成。8mL丸底フラスコ中へ、4-(4-[[2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エン-1-イル]メチル]ピペラジン-1-イル)-2-[14-チア-2,4,10-トリアザトリシクロ[7.5.0.0^[3,7]]テトラデカ-1(9),2,5,7-テトラエン-10-イル]安息香酸(30 mg、0.05 mmol、1当量)、3-ニトロ-4-[[(オキサン-4-イル)メチル]アミノ]ベンゼン-1-スルホンアミド(17 mg、0.06 mmol、1.20当量)、EDCI(18 mg、0.09 mmol、2当量)、DMAP(23 mg、0.19 mmol、4当量)、DCM(3mL)を入れた。得られる溶液を室温で一晩撹拌した。得られる混合物を濃縮した。粗生成物をFlash-Prep-HPLCにより以下の条件で精製した(IntelFlash-1):カラム、C18シリカゲル;移動相、水(0.1%FA)及びACN(48.0%ACNを7分で53.0%まで上昇させ、95.0%で1分維持し、1分で48.0%まで低下させる)で5分以内;検出器、UV 254 nm。これにより、10.6 mg(24.15%)の4-(4-[[2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エン-1-イル]メチル]ピペラジン-1-イル)-N-(3-ニトロ-4-[[(オキサン-4-イル)メチル]アミノ]ベンゼンスルホニル)-2-[14-チア-2,4,10-トリアザトリシクロ[7.5.0.0^[3,7]]テトラデカ-1(9),2,5,7-テトラエン-10-イル]ベンズアミドが黄色固体として得られた。LC-MS: (ES, m/z): M+1=939, R,T= 3.55 分.逆相カラム(C18)により保持時間の測定を行った。Shimadzu LCMS 2020; 50×3.0 Kinetex 2.6u XB-C18、2.6ミクロン;溶離液A:水(0.05% TFA);溶離液B:アセトニトリル;直線的グラジエント。H-NMR: (CDCl3, 300ppm): 8.71(s, 1H), 8.49 (s, 1H), 7.99-7.97(m, 1H), 7.81-7.77(m, 1H), 7.38-7.28(m, 4H), 7.01-6.93(m, 2H), 6.88-6.72(m, 3H), 3.36(s, 1H), 4.06-3.26(m, 18H), 2.73-2.22(m, 6H), 2.13-1.73(m, 3H), 1.79-1.25(m, 6H), 1.00(s, 6H). Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-N-(3-nitro-4-[[(oxan-4-yl)methyl]amino]benzenesulfonyl)-2-[14-thia-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradec-1(9),2,5,7-tetraen-10-yl]benzamide. Into an 8 mL round bottom flask was placed 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[14-thia-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradec-1(9),2,5,7-tetraen-10-yl]benzoic acid (30 mg, 0.05 mmol, 1 equiv), 3-nitro-4-[[(oxan-4-yl)methyl]amino]benzene-1-sulfonamide (17 mg, 0.06 mmol, 1.20 equiv), EDCI (18 mg, 0.09 mmol, 2 equiv), DMAP (23 mg, 0.19 mmol, 4 equiv), and DCM (3 mL). The resulting solution was stirred at room temperature overnight. The resulting mixture was concentrated. The crude product was purified by Flash-Prep-HPLC under the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, water (0.1% FA) and ACN (48.0% ACN ramped to 53.0% in 7 min, held at 95.0% for 1 min, ramped to 48.0% in 1 min) within 5 min; detector, UV 254 nm. This gave 10.6 mg (24.15%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-N-(3-nitro-4-[[(oxan-4-yl)methyl]amino]benzenesulfonyl)-2-[14-thia-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradec-1(9),2,5,7-tetraen-10-yl]benzamide as a yellow solid. LC-MS: (ES, m/z): M+1=939, R,T= 3.55 min. Retention time was measured using a reversed phase column (C18). Shimadzu LCMS 2020; 50×3.0 Kinetex 2.6u XB-C18, 2.6 micron; Eluent A: water (0.05% TFA); Eluent B: acetonitrile; linear gradient. H-NMR: (CDCl3, 300ppm): 8.71(s, 1H), 8.49 (s, 1H), 7.99-7.97(m, 1H), 7.81-7.77(m, 1H), 7.38-7.28(m, 4H), 7.01-6.93(m, 2H), 6.88-6.72(m, 3H), 3.36(s, 1H), 4.06-3.26(m, 18H), 2.73-2.22(m, 6H), 2.13-1.73(m, 3H), 1.79-1.25(m, 6H), 1.00(s, 6H).
[実施例6]
4-(4-[[2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エン-1-イル]メチル]ピペラジン-1-イル)-2-[14,14-ジオキソ-14]ラムダ6-チア-2,4,10-トリアザトリシクロ[7.5.0.0^[3,7]]テトラデカ-1(9),2,5,7-テトラエン-10-イル]-N-(3-ニトロ-4-[[(オキサン-4-イル)メチル]アミノ]ベンゼンスルホニル)ベンズアミドの調製
メチル4-(4-[[2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エン-1-イル]メチル]ピペラジン-1-イル)-2-[14,14-ジオキソ-14]ラムダ6-チア-2,4,10-トリアザトリシクロ[7.5.0.0^[3,7]]テトラデカ-1(9),2,5,7-テトラエン-10-イル]ベンゾエートの合成:8mL丸底フラスコ中へ、メチル4-(4-[[2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エン-1-イル]メチル]ピペラジン-1-イル)-2-[14-チア-2,4,10-トリアザトリシクロ[7.5.0.0^[3,7]]テトラデカ-1(9),2,5,7-テトラエン-10-イル]ベンゾエート(30 mg、0.046 mmol、1当量)、DCM(3 mL)、m-CPBA(19.72 mg、0.114 mmol、2.50当量)を入れた。得られる溶液を室温で一晩撹拌した。次いで1 mLの水を加えることにより反応をクエンチした。得られる溶液を2×5 mLの濃縮ジクロロメタンで抽出した。残渣を、酢酸エチル/石油エーテル(0:1~1:1)を使用してシリカゲルカラムに適用した。これにより20 mg(63.57%)のメチル4-(4-[[2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エン-1-イル]メチル]ピペラジン-1-イル)-2-[14,14-ジオキソ-14]ラムダ6-チア-2,4,10-トリアザトリシクロ[7.5.0.0^[3,7]]テトラデカ-1(9),2,5,7-テトラエン-10-イル]ベンゾエートが白色固体として得られた。LC-MS-PH-PHNW-4-65-8: (ES, m/z): M+1=688, R,T= 0.967 分.逆相カラム(C18)により保持時間の測定を行った。Shimadzu LCMS 2020; 50×3.0 Kinetex 2.6u XB-C18、2.6ミクロン;溶離液A:水(0.05% TFA);溶離液B:アセトニトリル;直線的グラジエント。
[Example 6]
Preparation of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[14,14-dioxo-14]lambda 6-thia-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradec-1(9),2,5,7-tetraen-10-yl]-N-(3-nitro-4-[[(oxan-4-yl)methyl]amino]benzenesulfonyl)benzamide Synthesis of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[14,14-dioxo-14]lambda 6-thia-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradec-1(9),2,5,7-tetraen-10-yl]benzoate: Into an 8 mL round-bottom flask, add methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[14-thia-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradec-1(9),2,5,7-tetraen-10-yl]benzoate (30 mg, 0.046 The resulting solution was stirred at room temperature overnight. The reaction was then quenched by adding 1 mL of water. The resulting solution was extracted with 2×5 mL of concentrated dichloromethane. The residue was applied to a silica gel column using ethyl acetate/petroleum ether (0:1 to 1:1). This gave 20 mg (63.57%) of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[14,14-dioxo-14]lambda 6-thia-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradec-1(9),2,5,7-tetraen-10-yl]benzoate as a white solid. LC-MS-PH-PHNW-4-65-8: (ES, m/z): M+1=688, R,T= 0.967 min. Retention time was measured on a reversed phase column (C18). Shimadzu LCMS 2020; 50×3.0 Kinetex 2.6u XB-C18, 2.6 micron; Eluent A: water (0.05% TFA); Eluent B: acetonitrile; linear gradient.
4-(4-[[2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エン-1-イル]メチル]ピペラジン-1-イル)-2-[14,14-ジオキソ-14]ラムダ6-チア-2,4,10-トリアザトリシクロ[7.5.0.0^[3,7]]テトラデカ-1(9),2,5,7-テトラエン-10-イル]安息香酸の合成。8mL丸底フラスコ中へ、メチル4-(4-[[2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エン-1-イル]メチル]ピペラジン-1-イル)-2-[14,14-ジオキソ-14]ラムダ6-チア-2,4,10-トリアザトリシクロ[7.5.0.0^[3,7]]テトラデカ-1(9),2,5,7-テトラエン-10-イル]ベンゾエート(20 mg、0.029 mmol、1当量)、1,4-ジオキサン(1 mL)、水(1 mL)、NaOH(6.97 mg、0.174 mmol、6.00当量)を入れた。得られる溶液を70℃で一晩撹拌した。HCl(1モル/L)で溶液のpH値を5に調整した。得られる溶液を2×3 mLの酢酸エチルで抽出した。有機層を2×3 mlのブラインで洗浄した。混合物を無水硫酸ナトリウム上で乾燥させ、濃縮した。これにより13 mg(66.35%)の4-(4-[[2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エン-1-イル]メチル]ピペラジン-1-イル)-2-[14,14-ジオキソ-14]ラムダ6-チア-2,4,10-トリアザトリシクロ[7.5.0.0^[3,7]]テトラデカ-1(9),2,5,7-テトラエン-10-イル]安息香酸が白色固体として得られた。LC-MS-PH-PHNW-4-65-9: (ES, m/z): M+1=674, R,T= 1.945 分.逆相カラム(C18)により保持時間の測定を行った。Shimadzu LCMS 2020; 50×3.0 Kinetex 2.6u XB-C18、2.6ミクロン;溶離液A:水(0.05% TFA);溶離液B:アセトニトリル;直線的グラジエント。 Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[14,14-dioxo-14]lambda 6-thia-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradec-1(9),2,5,7-tetraen-10-yl]benzoic acid. Into an 8 mL round bottom flask was placed methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[14,14-dioxo-14]lambda 6-thia-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradec-1(9),2,5,7-tetraen-10-yl]benzoate (20 mg, 0.029 mmol, 1 equiv.), 1,4-dioxane (1 mL), water (1 mL), and NaOH (6.97 mg, 0.174 mmol, 6.00 equiv.). The resulting solution was stirred at 70° C. overnight. The pH value of the solution was adjusted to 5 with HCl (1 mol/L). The resulting solution was extracted with 2×3 mL of ethyl acetate. The organic layer was washed with 2×3 ml of brine. The mixture was dried over anhydrous sodium sulfate and concentrated. This gave 13 mg (66.35%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[14,14-dioxo-14]lambda 6-thia-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradec-1(9),2,5,7-tetraen-10-yl]benzoic acid as a white solid. LC-MS-PH-PHNW-4-65-9: (ES, m/z): M+1=674, R,T= 1.945 min. Retention time was measured by reverse phase column (C18). Shimadzu LCMS 2020; 50×3.0 Kinetex 2.6u XB-C18, 2.6 microns; Eluent A: water (0.05% TFA); Eluent B: acetonitrile; linear gradient.
4-(4-[[2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エン-1-イル]メチル]ピペラジン-1-イル)-2-[14,14-ジオキソ-14]ラムダ6-チア-2,4,10-トリアザトリシクロ[7.5.0.0^[3,7]]テトラデカ-1(9),2,5,7-テトラエン-10-イル]-N-(3-ニトロ-4-[[(オキサン-4-イル)メチル]アミノ]ベンゼンスルホニル)ベンズアミドの合成。8mL丸底フラスコ中へ、3-ニトロ-4-[[(オキサン-4-イル)メチル]アミノ]ベンゼン-1-スルホンアミド(6.08 mg、0.019 mmol、1当量)、4-(4-[[2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エン-1-イル]メチル]ピペラジン-1-イル)-2-[14,14-ジオキソ-14]ラムダ6-チア-2,4,10-トリアザトリシクロ[7.5.0.0^[3,7]]テトラデカ-1(9),2,5,7-テトラエン-10-イル]安息香酸(13 mg、0.019 mmol、1当量)、DCM(0.47mL、5.506 mmol、381.56当量)、DMAP(9.42 mg、0.077 mmol、4当量)、EDCI(7.39 mg、0.039 mmol、2当量)を入れた。得られる溶液を室温で一晩撹拌した。得られる混合物を濃縮した。粗生成物を分取HPLCにより以下の条件でさらに精製した(Waters I):カラム、Xbridge Prep C18 OBD カラム、5 um、19×150 mm;移動相、水(0.05% TFA)及びCH3CN(46% CH3CNを7分で51%まで上昇させる);検出器、UV 220及び254 nm。これにより2.5 mg(6.24%)の4-(4-[[2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エン-1-イル]メチル]ピペラジン-1-イル)-2-[14,14-ジオキソ-14]ラムダ6-チア-2,4,10-トリアザトリシクロ[7.5.0.0^[3,7]]テトラデカ-1(9),2,5,7-テトラエン-10-イル]-N-(3-ニトロ-4-[[(オキサン-4-イル)メチル]アミノ]ベンゼンスルホニル)ベンズアミドが黄色固体として得られた。LC-MS-PH-PHNW-4-65-0: (ES, m/z): M+1=971.5, R,T= 3.243 分. 逆相カラム(C18)により保持時間の測定を行った。Shimadzu LCMS 2020; 50×3.0 Kinetex 2.6u XB-C18、2.6ミクロン;溶離液A:水(0.05% TFA);溶離液B:アセトニトリル;直線的グラジエント Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[14,14-dioxo-14]lambda 6-thia-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradec-1(9),2,5,7-tetraen-10-yl]-N-(3-nitro-4-[[(oxan-4-yl)methyl]amino]benzenesulfonyl)benzamide. Into an 8 mL round-bottom flask was added 3-nitro-4-[[(oxan-4-yl)methyl]amino]benzene-1-sulfonamide (6.08 mg, 0.019 mmol, 1 equiv.), 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[14,14-dioxo-14]lambda 6-thia-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradec-1(9),2,5,7-tetraen-10-yl]benzoic acid (13 mg, 0.019 mmol, 1 equiv.), DCM (0.47 mL, 5.506 mmol, 381.56 equiv.), DMAP (9.42 mg, 0.077 mmol, 4 equiv.), EDCI (7.39 mg, 0.039 mmol, 2 equiv.). The resulting solution was stirred at room temperature overnight. The resulting mixture was concentrated. The crude product was further purified by preparative HPLC using the following conditions (Waters I): column, Xbridge Prep C18 OBD column, 5 um, 19×150 mm; mobile phase, water (0.05% TFA) and CH 3 CN (46% CH 3 CN ramped to 51% in 7 min); detector, UV 220 and 254 nm. This gave 2.5 mg (6.24%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[14,14-dioxo-14]lambda 6-thia-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradec-1(9),2,5,7-tetraen-10-yl]-N-(3-nitro-4-[[(oxan-4-yl)methyl]amino]benzenesulfonyl)benzamide as a yellow solid. LC-MS-PH-PHNW-4-65-0: (ES, m/z): M+1=971.5, R,T= 3.243 min. Retention time was measured using a reversed phase column (C18). Shimadzu LCMS 2020; 50×3.0 Kinetex 2.6u XB-C18, 2.6 micron; Eluent A: water (0.05% TFA); Eluent B: acetonitrile; linear gradient
[実施例7]
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3-メトキシ-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミドの調製
2-メトキシプロパン-1,3-ジオールの合成。窒素の不活性雰囲気でパージされ維持された1000mL三つ口丸底フラスコ中へ、1,3-ジメチル2-メトキシプロパンジオエート(20 g、123 mmol、1当量)及びTHF(250 mL)を入れた。LiAlH4(23.4 g、616 mmol、5.0当量)を氷浴で少しずつ加えた。得られる溶液を室温で16時間撹拌した。この反応が完了した後、23.4 mLの水を加えることにより反応混合物をクエンチし、23.4 mLのNaOH(H20中10%)及び70 mLの水を氷浴で溶液に逐次的に加えた。固体をろ過した。得られる混合物を真空下で濃縮した。これにより12 g(91.67%)の2-メトキシプロパン-1,3-ジオールが無色油状物として得られた。1H NMR (300 MHz, CDCL3, ppm) δ 3.80-3.63 (m, 4H), 3.47 (s, 3H), 3.36-3.32 (m, 1H), 3.25 (bs, 2H).
[Example 7]
Preparation of 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methoxy-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide
Synthesis of 2-methoxypropane-1,3-diol. In a 1000 mL three-necked round bottom flask purged and maintained with an inert atmosphere of nitrogen, 1,3-dimethyl 2-methoxypropanedioate (20 g, 123 mmol, 1 equiv.) and THF (250 mL) were placed. LiAlH4 (23.4 g, 616 mmol, 5.0 equiv.) was added portionwise in an ice bath. The resulting solution was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was quenched by adding 23.4 mL of water, and 23.4 mL of NaOH (10% in H2O ) and 70 mL of water were added sequentially to the solution in an ice bath. The solid was filtered. The resulting mixture was concentrated under vacuum. This gave 12 g (91.67%) of 2-methoxypropane-1,3-diol as a colorless oil. 1H NMR (300 MHz, CDCL3 , ppm) δ 3.80-3.63 (m, 4H), 3.47 (s, 3H), 3.36-3.32 (m, 1H), 3.25 (bs, 2H).
3-(5-ブロモ-1-((2-(トリメチルシリル)エトキシ)メチル)-1H-ピロロ[2,3-b]ピリジン-6-イルオキシ)-2-メトキシプロパン-1-オールの合成。250mL三つ口丸底フラスコ中へ、2-メトキシプロパン-1,3-ジオール(1.84 g、17.4 mmol、1.2当量)及びTHF(70 mL)を入れ、NaH(0.87 g、36.2 mmol、2.5当量)を氷浴で加え、混合物を室温で30分間撹拌した後、次いで5-ブロモ-6-フルオロ-1-[[2-(トリメチルシリル)エトキシ]メチル]-1H-ピロロ[2,3-b]ピリジン(5.0 g、14.5 mmol、1当量)を室温で加えた。得られる溶液を80度で4時間撹拌した。次いで、20 mLの水を加えることにより反応をクエンチした。得られる溶液を3×50 mLのジクロロメタンで抽出し、有機層を合わせた。得られる混合物を1×50 mLのブラインで洗浄した。混合物を無水硫酸ナトリウム上で乾燥させた。固体をろ過した。得られる混合物を濃縮した。残渣を、酢酸エチル/石油エーテル(0~40%)を使用してシリカゲルカラムに適用した。これにより4.0 g(64.03%)の3-[(5-ブロモ-1-[[2-(トリメチルシリル)エトキシ]メチル]-1H-ピロロ[2,3-b]ピリジン-6-イル)オキシ]-2-メトキシプロパン-1-オールが白色固体として得られた。1H NMR (300 MHz, CDCL3, ppm) 8.09 (s, 1H), 7.20 (d, J=3.6 Hz, 1H), 6.44 (d, J=3.6 Hz, 1H), 5.62 (s, 2H), 4.60-4.58 (m, 2H), 3.97-3.95 (m, 1H), 3.92-3.90 (m, 2H), 3.79 (s, 3H), 3.65-3.60 (m, 2H), 0.98-0.93 (m, 2H), 0.01 (s, 9H). Synthesis of 3-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-6-yloxy)-2-methoxypropan-1-ol. In a 250 mL three-neck round bottom flask, 2-methoxypropane-1,3-diol (1.84 g, 17.4 mmol, 1.2 eq.) and THF (70 mL) were placed, NaH (0.87 g, 36.2 mmol, 2.5 eq.) was added in an ice bath, the mixture was stirred at room temperature for 30 minutes, and then 5-bromo-6-fluoro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridine (5.0 g, 14.5 mmol, 1 eq.) was added at room temperature. The resulting solution was stirred at 80° C. for 4 hours. The reaction was then quenched by adding 20 mL of water. The resulting solution was extracted with 3×50 mL of dichloromethane and the organic layers were combined. The resulting mixture was washed with 1×50 mL of brine. The mixture was dried over anhydrous sodium sulfate. The solids were filtered. The resulting mixture was concentrated. The residue was applied to a silica gel column with ethyl acetate/petroleum ether (0-40%). This gave 4.0 g (64.03%) of 3-[(5-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-6-yl)oxy]-2-methoxypropan-1-ol as a white solid. 1H NMR (300 MHz, CDCL3 , ppm): 8.09 (s, 1H), 7.20 (d, J=3.6 Hz, 1H), 6.44 (d, J=3.6 Hz, 1H), 5.62 (s, 2H), 4.60-4.58 (m, 2H), 3.97-3.95 (m, 1H), 3.92-3.90 (m, 2H), 3.79 (s, 3H), 3.65-3.60 (m, 2H), 0.98-0.93 (m, 2H), 0.01 (s, 9H).
N-(6-(3-ヒドロキシ-2-メトキシプロポキシ)-1-((2-(トリメチルシリル)エトキシ)メチル)-1H-ピロロ[2,3-b]ピリジン-5-イル)-4-メチルベンゼンスルホンアミドの合成。窒素の不活性雰囲気でパージされ維持された250mL三つ口丸底フラスコ中へ、3-[(5-ブロモ-1-[[2-(トリメチルシリル)エトキシ]メチル]-1H-ピロロ[2,3-b]ピリジン-6-イル)オキシ]-2-メトキシプロパン-1-オール(4.0 g、9.3 mmol、1当量)、Ts-NH2(4.76 g、27.8 mmol、3.00当量)、Cs2CO3(9.06 g、27.8 mmol、3.0当量)、CuI(0.88 g、4.6 mmol、0.5当量)、1,10-フェナントロリン(0.50 g、2.8 mmol、0.3当量)及びDMSO(100 mL)を入れた。得られる溶液を油浴中で120度で24時間撹拌した。反応混合物を冷却した。得られる溶液を500 mlのDCMで希釈した。固体をろ過した。混合物を無水硫酸ナトリウム上で乾燥させた。固体をろ過した。得られる混合物を濃縮した。残渣を、酢酸エチル/石油エーテル(0~60%)を使用してシリカゲルカラムに適用した。これにより2.7 g(55.82%)のN-[6-(3-ヒドロキシ-2-メトキシプロポキシ)-1-[[2-(トリメチルシリル)エトキシ]メチル]-1H-ピロロ[2,3-b]ピリジン-5-イル]-4-メチルベンゼン-1-スルホンアミドが固体として得られた。1H NMR (300 MHz, CDCL3, ppm) 8.09 (s, 1H), 7.61-7.59 (m, 2H), 7.17-7.15 (m, 3H), 6.75 (s, 1H), 6.46 (d, J=3.3 Hz, 1H), 5.48 (s, 2H), 4.28-4.23 (m, 2H), 3.59-3.44 (m, 8H), 2.37 (s, 3H), 0.92-0.86 (m, 3H), 0.01 (s, 9H). Synthesis of N-(6-(3-hydroxy-2-methoxypropoxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-methylbenzenesulfonamide. Into a 250 mL three-necked round bottom flask purged and maintained with an inert atmosphere of nitrogen was placed 3-[(5-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-6-yl)oxy]-2-methoxypropan-1-ol (4.0 g, 9.3 mmol, 1 equiv.), Ts-NH2 (4.76 g, 27.8 mmol, 3.00 equiv.), Cs2CO3 ( 9.06 g, 27.8 mmol, 3.0 equiv.), CuI (0.88 g, 4.6 mmol, 0.5 equiv.), 1,10-phenanthroline (0.50 g, 2.8 mmol, 0.3 equiv.) and DMSO (100 mL). The resulting solution was stirred in an oil bath at 120° C. for 24 hours. The reaction mixture was cooled. The resulting solution was diluted with 500 ml of DCM. The solid was filtered off. The mixture was dried over anhydrous sodium sulfate. The solid was filtered off. The resulting mixture was concentrated. The residue was applied to a silica gel column with ethyl acetate/petroleum ether (0-60%). This gave 2.7 g (55.82%) of N-[6-(3-hydroxy-2-methoxypropoxy)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-4-methylbenzene-1-sulfonamide as a solid. 1H NMR (300 MHz, CDCL3 , ppm): 8.09 (s, 1H), 7.61-7.59 (m, 2H), 7.17-7.15 (m, 3H), 6.75 (s, 1H), 6.46 (d, J=3.3 Hz, 1H), 5.48 (s, 2H), 4.28-4.23 (m, 2H), 3.59-3.44 (m, 8H), 2.37 (s, 3H), 0.92-0.86 (m, 3H), 0.01 (s, 9H).
3-メトキシ-1-トシル-7-((2-(トリメチルシリル)エトキシ)メチル)-1,3,4,7-テトラヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼパンの合成。窒素の不活性雰囲気でパージされ維持された100mL三つ口丸底フラスコ中へ、N-[6-(3-ヒドロキシ-2-メトキシプロポキシ)-1-[[2-(トリメチルシリル)エトキシ]メチル]-1H-ピロロ[2,3-b]ピリジン-5-イル]-4-メチルベンゼン-1-スルホンアミド(500 mg、0.96 mmol、1当量)、PPh3(1.2 g、4.79 mmol、5.0当量)及びTHF(10 mL)を入れ、DEAD(834 mg、4.79 mmol、5.0当量)を氷浴で滴下して加えた。得られる溶液を室温で2時間撹拌した。得られる溶液を50 mLのDCMで希釈した。得られる混合物を3×20 mlの水及び1×20 mLのブラインで洗浄した。混合物を無水硫酸ナトリウム上で乾燥させた。固体をろ過した。得られる混合物を真空下で濃縮した。残渣を、酢酸エチル/石油(0~60%)エーテルを使用してシリカゲルカラムに適用した。これにより370 mg(76.65%)の3-メトキシ-1-トシル-7-((2-(トリメチルシリル)エトキシ)メチル)-1,3,4,7-テトラヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピンが白色固体として得られた。LC-MS: (ES, m/z): M+H=504, R,T= 2.40分. Synthesis of 3-methoxy-1-tosyl-7-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepane. In a 100 mL three-necked round bottom flask purged and maintained with an inert atmosphere of nitrogen, N-[6-(3-hydroxy-2-methoxypropoxy)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-4-methylbenzene-1-sulfonamide (500 mg, 0.96 mmol, 1 equiv.), PPh3 (1.2 g, 4.79 mmol, 5.0 equiv.), and THF (10 mL) were added dropwise to DEAD (834 mg, 4.79 mmol, 5.0 equiv.) in an ice bath. The resulting solution was stirred at room temperature for 2 hours. The resulting solution was diluted with 50 mL of DCM. The resulting mixture was washed with 3×20 ml of water and 1×20 mL of brine. The mixture was dried over anhydrous sodium sulfate. The solid was filtered. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column using ethyl acetate/petroleum (0-60%) ether. This gave 370 mg (76.65%) of 3-methoxy-1-tosyl-7-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine as a white solid. LC-MS: (ES, m/z): M+H=504, R,T= 2.40 min.
3-メトキシ-7-((2-(トリメチルシリル)エトキシ)メチル)-1,3,4,7-テトラヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼパンの合成。250mL三つ口丸底フラスコ中へ、N2下でNa(158 mg、6.9 mmol、1.0当量)、ナフタレン(884 mg、6.9 mmol、10当量)及びDME(3ml)を入れた。Na及びナフタレンが完全に溶解するまで反応混合物を室温で撹拌した。これに3-メトキシ-1-トシル-7-((2-(トリメチルシリル)エトキシ)メチル)-1,3,4,7-テトラヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン(350 mg、0.69 mmol、1当量)のTHF(5mL)中の溶液を-78℃で加えた。出発物質がTLCにより消費されるまで得られる溶液を-60℃~-40℃で2~3時間撹拌した。次いで、5 mLのNH4Clを-10℃で加えることにより反応をクエンチした。得られる溶液を3×10 mLの酢酸エチルで抽出した。混合物を無水硫酸ナトリウム上で乾燥させ、真空下で濃縮した。残渣をシリカゲルカラムに適用し、酢酸エチル/石油エーテル(1/3)で溶出した。これにより214 mg(88%)の3-メトキシ-7-((2-(トリメチルシリル)エトキシ)メチル)-1,3,4,7-テトラヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピンが白色固体として得られた。LC-MS: (ES, m/z): M+H=350, R,T= 2.26分. Synthesis of 3-methoxy-7-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepane. In a 250 mL three-necked round-bottom flask was placed Na (158 mg, 6.9 mmol, 1.0 equiv), naphthalene (884 mg, 6.9 mmol, 10 equiv) and DME (3 ml) under N2 . The reaction mixture was stirred at room temperature until Na and naphthalene were completely dissolved. To this was added a solution of 3-methoxy-1-tosyl-7-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine (350 mg, 0.69 mmol, 1 equiv.) in THF (5 mL) at -78°C. The resulting solution was stirred at -60°C to -40°C for 2-3 h until the starting material was consumed by TLC. The reaction was then quenched by adding 5 mL of NH 4 Cl at -10°C. The resulting solution was extracted with 3 x 10 mL of ethyl acetate. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied to a silica gel column and eluted with ethyl acetate/petroleum ether (1/3). This gave 214 mg (88%) of 3-methoxy-7-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine as a white solid. LC-MS: (ES, m/z): M+H=350, R,T= 2.26 min.
メチル4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3-メトキシ-7-((2-(トリメチルシリル)エトキシ)メチル)-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンゾエートの合成。窒素の不活性雰囲気でパージされ維持された100mL丸底フラスコ中へ、メチル2-ブロモ-4-(4-[[2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エン-1-イル]メチル]ピペラジン-1-イル)ベンゾエート(1.34 g、2.52 mmol、4.00当量)、トルエン(20 mL)、3-メトキシ-7-((2-(トリメチルシリル)エトキシ)メチル)-1,3,4,7-テトラヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン(220 mg、0.63 mmol、1当量)、Cs2CO3(1.02 g、3.15 mmol、5当量)、XantPhos Pd 2G(25 mg、0.06 mmol、0.1当量)を入れた。得られる溶液を110℃で一晩撹拌した。得られる溶液を30 mLの水で希釈した。得られる溶液を2×30 mLの酢酸エチルで抽出した。得られる混合物を1×30 mLのブラインで洗浄した。混合物を無水硫酸ナトリウム上で乾燥させ、真空下で濃縮した。残渣を、酢酸エチル/石油エーテル(0~50%)を使用してシリカゲルカラムに適用した。これにより403 mgの粗製(80.0%)メチル4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3-メトキシ-7-((2-(トリメチルシリル)エトキシ)メチル)-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンゾエートが黄色固体として得られた。 Synthesis of methyl 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methoxy-7-((2-(trimethylsilyl)ethoxy)methyl)-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzoate. Into a 100 mL round bottom flask purged and maintained with an inert atmosphere of nitrogen was placed methyl 2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)benzoate (1.34 g, 2.52 mmol, 4.00 equiv.), toluene (20 mL), 3-methoxy- 7 -((2-(trimethylsilyl)ethoxy)methyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine (220 mg, 0.63 mmol, 1 equiv.), Cs2CO3 (1.02 g, 3.15 mmol, 5 equiv.), and XantPhos Pd 2G (25 mg, 0.06 mmol, 0.1 equiv.). The resulting solution was stirred at 110° C. overnight. The resulting solution was diluted with 30 mL of water. The resulting solution was extracted with 2×30 mL of ethyl acetate. The resulting mixture was washed with 1×30 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied to a silica gel column using ethyl acetate/petroleum ether (0-50%). This gave 403 mg of crude (80.0%) methyl 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methoxy-7-((2-(trimethylsilyl)ethoxy)methyl)-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzoate as a yellow solid.
メチル4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3-メトキシ-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンゾエートの合成。40mLバイアル中へ、メチル4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3-メトキシ-7-((2-(トリメチルシリル)エトキシ)メチル)-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンゾエート(380 mg、0.48 mmol、1当量)、THF(20 mL)、TBAF.3H2O(756 mg、2.4 mmol、5当量)、エタン-1,2-ジアミン(576 mg、9.6 mmol、20当量)を入れた。得られる溶液を油浴中で70℃で一晩撹拌した。得られる溶液を20 mLの水で希釈した。得られる溶液を3×30 mLの酢酸エチルで抽出した。得られる混合物を2×20 mLのブラインで洗浄した。混合物を無水硫酸ナトリウム上で乾燥させ、真空下で濃縮した。残渣を、酢酸エチル/石油エーテル(0~50%)を使用してシリカゲルカラムに適用した。これにより338 mg(93%)のメチル4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3-メトキシ-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンゾエートが淡黄色固体として得られた。LC-MS: (ES, m/z): M+H=670, R,T= 2.00分. Synthesis of methyl 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methoxy-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzoate. Into a 40 mL vial was placed methyl 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methoxy-7-((2-(trimethylsilyl)ethoxy)methyl)-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzoate (380 mg, 0.48 mmol, 1 equiv.), THF (20 mL), TBAF.3H2O (756 mg, 2.4 mmol, 5 equiv.), and ethane-1,2-diamine (576 mg, 9.6 mmol, 20 equiv.). The resulting solution was stirred overnight at 70°C in an oil bath. The resulting solution was diluted with 20 mL of water. The resulting solution was extracted with 3×30 mL of ethyl acetate. The resulting mixture was washed with 2×20 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate/petroleum ether (0-50%). This afforded 338 mg (93%) of methyl 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methoxy-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzoate as a pale yellow solid. LC-MS: (ES, m/z): M+H=670, R,T= 2.00 min.
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3-メトキシ-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)安息香酸の合成。40mLバイアル中へ、メチル4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3-メトキシ-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンゾエート(200 mg、0.30 mmol、1当量)、MeOH(6 mL)、1,4-ジオキサン(6 mL)、H2O(2 mL)、NaOH(72 mg、1.8 mmol、6.00当量)を入れた。得られる溶液を油浴中で60℃で一晩撹拌した。得られる混合物を真空下で濃縮した。HCl(2モル/L)で溶液のpH値を5~6に調整した。得られる溶液を2×50 mLのジクロロメタン/MeOH(v:v=10:l)で抽出した。得られる混合物を2×200 mLのブラインで洗浄した。混合物を無水硫酸ナトリウム上で乾燥させ、真空下で濃縮した。これにより152 mg(81.0%)の4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3-メトキシ-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)安息香酸が淡黄色固体として得られた。LC-MS: (ES, m/z): M+H=656, R,T= 2.43分. Synthesis of 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methoxy-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzoic acid. In a 40 mL vial, methyl 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methoxy-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzoate (200 mg, 0.30 mmol, 1 equiv.), MeOH (6 mL), 1,4-dioxane (6 mL), H2O (2 mL), NaOH (72 mg, 1.8 mmol, 6.00 equiv.) were added. The resulting solution was stirred overnight at 60°C in an oil bath. The resulting mixture was concentrated under vacuum. The pH value of the solution was adjusted to 5-6 with HCl (2 mol/L). The resulting solution was extracted with 2×50 mL of dichloromethane/MeOH (v:v=10:l). The resulting mixture was washed with 2×200 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This afforded 152 mg (81.0%) of 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methoxy-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzoic acid as a pale yellow solid. LC-MS: (ES, m/z): M+H=656, R,T= 2.43 min.
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3-メトキシ-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミドの合成。40mL丸底フラスコ中へ、4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3-メトキシ-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)安息香酸(50 mg、0.08 mmol、1当量)、DCM(3 mL)、3-ニトロ-4-[[(オキサン-4-イル)メチル]アミノ]ベンゼン-1-スルホンアミド(25.2 mg、0.08 mmol、1.00当量)、EDCI(30.6 mg、0.16 mmol、2当量)、DMAP(39.0 mg、0.32 mmol、4当量)を入れた。得られる溶液を25度で一晩撹拌した。得られる混合物を真空下で濃縮した。残渣を、ジクロロメタン/メタノール(10:1)を使用してシリカゲルカラムに適用した。粗生成物をFlash-Prep-HPLCにより以下の条件で精製した(IntelFlash-1):カラム、C18逆相カラム;移動相、水(10M MOL/LNH4HCO3+0.05%NH3.H2O)及びCH3CN(20.0% CH3CNを30分で90.0%まで上昇させる);検出器、UV 220 nm。これにより32 mg(40.0%)の4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3-メトキシ-3,4-ジヒドロ-2H-ピロロ[3'2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミドが黄色固体として得られた。LC-MS: (ES, m/z): M+1=953, R,T= 3.44分. 1H NMR (300 MHz, DMSO-d6, ppm) δ 11.00 (ds, 1H), 8.56 (s, 2H), 7.47-7.44 (m, 2H), 7.36-7.33 (m, 2H), 7.08-7.04 (m, 3H), 6.78-6..65 (m, 2H), 6.57-6.54 (m, 1H), 6.43 (s, 1H), 6.04 (s, 1H), 4.05-3.15 (m, 20H), 3.13 (s, 1H), 2.70-2.35 (m, 4H), 2.03 (s, 3H), 1.92-1.90 (m, 1H), 1.89-1.87 (m, 2H), 1.71-1.67 (m, 2H), 1.53-1.45 (m, 3H), 0.97 (s, 6H). Synthesis of 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methoxy-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide. Into a 40 mL round bottom flask was placed 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methoxy-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzoic acid (50 mg, 0.08 mmol, 1 equiv.), DCM (3 mL), 3-nitro-4-[[(oxan-4-yl)methyl]amino]benzene-1-sulfonamide (25.2 mg, 0.08 mmol, 1.00 equiv.), EDCI (30.6 mg, 0.16 mmol, 2 equiv.), and DMAP (39.0 mg, 0.32 mmol, 4 equiv.). The resulting solution was stirred at 25° overnight. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column using dichloromethane/methanol (10:1). The crude product was purified by Flash-Prep-HPLC under the following conditions (IntelFlash-1): column, C18 reverse phase column; mobile phase, water ( 10M MOL/ LNH4HCO3 + 0.05% NH3.H2O ) and CH3CN (20.0% CH3CN increased to 90.0% in 30 min); detector, UV 220 nm . This gave 32 mg (40.0%) of 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methoxy-3,4-dihydro-2H-pyrrolo[3'2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide as a yellow solid. LC-MS: (ES, m/z): M+1=953, R,T= 3.44 min. 1H NMR (300 MHz, DMSO-d6 , ppm) δ 11.00 (ds, 1H), 8.56 (s, 2H), 7.47-7.44 (m, 2H), 7.36-7.33 (m, 2H), 7.08-7.04 (m, 3H), 6.78-6..65 (m, 2H), 6.57-6.54 (m, 1H), 6.43 (s, 1H), 6.04 (s, 1H), 4.05-3.15 (m, 20H), 3.13 (s, 1H), 2.70-2.35 (m, 4H), 2.03 (s, 3H), 1.92-1.90 (m, 1H), 1.89-1.87 (m, 2H), 1.71-1.67 (m, 2H), 1.53-1.45 (m, 3H), 0.97 (s, 6H).
[実施例8]
4-(4-[[2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エン-1-イル]メチル]ピペラジン-1-イル)-N-[4-([[(2R)-1,4-ジオキサン-2-イル]メチル]アミノ)-3-ニトロベンゼンスルホニル]-2-[14-オキサ-2,4,10-トリアザトリシクロ[7.5.0.0^[3,7]]テトラデカ-1(9),2,5,7-テトラエン-10-イル]ベンズアミドの調製
4-([[(2R)-1,4-ジオキサン-2-イル]メチル]アミノ)-3-ニトロベンゼン-1-スルホンアミドの合成。100-mL丸底フラスコ中へ、4-フルオロ-3-ニトロベンゼン-1-スルホンアミド(1.43 g、0.007 mmol、1当量)、1-[(2R)-1,4-ジオキサン-2-イル]メタンアミン塩酸塩(1 g、6.510 mmol、1当量)、THF(30 mL)、Cs2CO3(8.48 g、0.026 mmol、4当量)を入れた。得られる溶液を油浴中で50℃で一晩撹拌した。固体をろ過によって回収した。固体を乾燥器内で減圧下で乾燥させた。これにより1.8 g(87.14%)の4-([[(2R)-1,4-ジオキサン-2-イル]メチル]アミノ)-3-ニトロベンゼン-1-スルホンアミドが黄色固体として得られた。LC-MS: (ES, m/z): M+1=318, R,T= 0.740分.ee=99%、[a]=+10.9(100 mlのDMSO中C=0.103 g、T=27℃)。
[Example 8]
Preparation of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-N-[4-([[(2R)-1,4-dioxan-2-yl]methyl]amino)-3-nitrobenzenesulfonyl]-2-[14-oxa-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradec-1(9),2,5,7-tetraen-10-yl]benzamide
Synthesis of 4-([[(2R)-1,4-dioxan-2-yl]methyl]amino)-3-nitrobenzene-1-sulfonamide. In a 100-mL round-bottom flask were placed 4-fluoro-3-nitrobenzene-1-sulfonamide (1.43 g, 0.007 mmol, 1 equiv.), 1-[(2R)-1,4-dioxan-2-yl] methanamine hydrochloride (1 g, 6.510 mmol, 1 equiv.), THF (30 mL), and Cs2CO3 (8.48 g, 0.026 mmol, 4 equiv.). The resulting solution was stirred overnight at 50°C in an oil bath. The solid was collected by filtration. The solid was dried in an oven under reduced pressure. This gave 1.8 g (87.14%) of 4-([[(2R)-1,4-dioxan-2-yl]methyl]amino)-3-nitrobenzene-1-sulfonamide as a yellow solid. LC-MS: (ES, m/z): M+1=318, R,T= 0.740 min. ee=99%, [a]=+10.9 (C=0.103 g in 100 ml DMSO, T=27° C.).
メチル4-(4-[[2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エン-1-イル]メチル]ピペラジン-1-イル)-2-(4-[[2-(トリメチルシリル)エトキシ]メチル]-14-オキサ-2,4,10-トリアザトリシクロ[7.5.0.0^[3,7]]テトラデカ-1(9),2,5,7-テトラエン-10-イル)ベンゾエートの合成。窒素の不活性雰囲気でパージされ維持された100mL丸底フラスコ中へ、メチル2-ブロモ-4-(4-[[2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エン-1-イル]メチル]ピペラジン-1-イル)ベンゾエート(4.35 g、8.21 mmol、1.87当量)、トルエン(50 mL)、4-[[2-(トリメチルシリル)エトキシ]メチル]-14-オキサ-2,4,10-トリアザトリシクロ[7.5.0.0^[3,7]]テトラデカ-1(9),2,5,7-テトラエン(1.4 g、4.39 mmol、1当量)、Cs2CO3(7.1 g、21.85 mmol、4.98当量)、XantPhos Pd 2G(584 mg、0.66 mmol、0.15当量)を入れた。得られる溶液を110℃で一晩撹拌した。得られる溶液を300 mLの水で希釈した。得られる溶液を2×100 mLの酢酸エチルで抽出した。得られる混合物を1×300 mLのブラインで洗浄した。混合物を無水硫酸ナトリウム上で乾燥させ、真空下で濃縮した。残渣を、酢酸エチル/石油エーテル(1:2)を使用してシリカゲルカラムに適用した。これにより2.1 g(62%)のメチル4-(4-[[2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エン-1-イル]メチル]ピペラジン-1-イル)-2-(4-[[2-(トリメチルシリル)エトキシ]メチル]-14-オキサ-2,4,10-トリアザトリシクロ[7.5.0.0^[3,7]]テトラデカ-1(9),2,5,7-テトラエン-10-イル)ベンゾエートが褐色固体として得られた。LC-MS: (ES, m/z): M+H=770, R,T= 1.318分. Synthesis of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-(4-[[2-(trimethylsilyl)ethoxy]methyl]-14-oxa-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradec-1(9),2,5,7-tetraen-10-yl)benzoate. Into a 100 mL round bottom flask purged and maintained with an inert atmosphere of nitrogen was placed methyl 2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)benzoate (4.35 g, 8.21 mmol, 1.87 equiv), toluene (50 mL), 4-[[2-(trimethylsilyl)ethoxy]methyl]-14-oxa-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradeca-1(9),2,5,7-tetraene (1.4 g, 4.39 mmol, 1 equiv), Cs2CO3 ( 7.1 g, 21.85 mmol, 4.98 equiv), and XantPhos Pd 2G (584 mg, 0.66 mmol, 0.15 equiv). The resulting solution was stirred at 110° C. overnight. The resulting solution was diluted with 300 mL of water. The resulting solution was extracted with 2×100 mL of ethyl acetate. The resulting mixture was washed with 1×300 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied to a silica gel column using ethyl acetate/petroleum ether (1:2). This gave 2.1 g (62%) of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-(4-[[2-(trimethylsilyl)ethoxy]methyl]-14-oxa-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradec-1(9),2,5,7-tetraen-10-yl)benzoate as a brown solid. LC-MS: (ES, m/z): M+H=770, R,T= 1.318 min.
メチル4-(4-[[2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エン-1-イル]メチル]ピペラジン-1-イル)-2-[14-オキサ-2,4,10-トリアザトリシクロ[7.5.0.0^[3,7]]テトラデカ-1(9),2,5,7-テトラエン-10-イル]ベンゾエートの合成。40mLバイアル中へ、メチル4-(4-[[2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エン-1-イル]メチル]ピペラジン-1-イル)-2-(4-[[2-(トリメチルシリル)エトキシ]メチル]-14-オキサ-2,4,10-トリアザトリシクロ[7.5.0.0^[3,7]]テトラデカ-1(9),2,5,7-テトラエン-1(2.1 g、3.29 mmol、1当量)、THF(20 mL)、TBAF.3H20(5 g)、エタン-1,2-ジアミン(1.4 g)を入れた。得られる溶液を油浴中で70℃で一晩撹拌した。得られる溶液を200 mLの水で希釈した。得られる溶液を3×30 mLの酢酸エチルで抽出した。得られる混合物を2×200 mLのブラインで洗浄した。混合物を無水硫酸ナトリウム上で乾燥させ、真空下で濃縮した。残渣を、酢酸エチル/石油エーテル(1:5)を使用して再結晶化した。これにより1.4 g(80%)のメチル4-(4-[[2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エン-1-イル]メチル]ピペラジン-1-イル)-2-[14-オキサ-2,4,10-トリアザトリシクロ[7.5.0.0^[3,7]]テトラデカ-1(9),2,5,7-テトラエン-10-イル]ベンゾエートが白色固体として得られた。LC-MS: (ES, m/z): M+H=640, R,T= 1.023分. Synthesis of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[14-oxa-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradec-1(9),2,5,7-tetraen-10-yl]benzoate. Into a 40 mL vial was placed methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-(4-[[2-(trimethylsilyl)ethoxy]methyl]-14-oxa-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradeca-1(9),2,5,7-tetraene-1 (2.1 g, 3.29 mmol, 1 equiv.), THF (20 mL), TBAF.3H 2 0 (5 g), and ethane-1,2-diamine (1.4 g). The resulting solution was stirred overnight at 70° C. in an oil bath. The resulting solution was diluted with 200 mL of water. The resulting solution was extracted with 3×30 mL of ethyl acetate. The resulting mixture was diluted with 2×200 mL of water. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was recrystallized using ethyl acetate/petroleum ether (1:5). This gave 1.4 g (80%) of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[14-oxa-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradec-1(9),2,5,7-tetraen-10-yl]benzoate as a white solid. LC-MS: (ES, m/z): M+H=640, R,T= 1.023 min.
4-(4-[[2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エン-1-イル]メチル]ピペラジン-1-イル)-2-[14-オキサ-2,4,10-トリアザトリシクロ[7.5.0.0^[3,7]]テトラデカ-1(9),2,5,7-テトラエン-10-イル]安息香酸の合成。40mLバイアル中へ、メチル4-(4-[[2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エン-1-イル]メチル]ピペラジン-1-イル)-2-[14-オキサ-2,4,10-トリアザトリシクロ[7.5.0.0^[3,7]]テトラデカ-1(9),2,5,7-テトラエン-10-イル]ベンゾエート(1.4 g、2.24 mmol、1当量)、EtOH(25 mL)、ジオキサン(25 mL)、4M NaOH(5 mL)を入れた。得られる溶液を油浴中で80℃で4時間撹拌した。得られる混合物を真空下で濃縮した。HCl(2モル/L)で溶液のpH値を5~6に調整した。固体をろ過によって回収した。これにより1.1 g(80%)の4-(4-[[2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エン-1-イル]メチル]ピペラジン-1-イル)-2-[14-オキサ-2,4,10-トリアザトリシクロ[7.5.0.0^[3,7]]テトラデカ-1(9),2,5,7-テトラエン-10-イル]安息香酸が白色固体として得られた。LC-MS: (ES, m/z): M+H=626, R,T= 2.138分. Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[14-oxa-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradec-1(9),2,5,7-tetraen-10-yl]benzoic acid. In a 40 mL vial, methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[14-oxa-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradec-1(9),2,5,7-tetraen-10-yl]benzoate (1.4 g, 2.24 mmol, 1 equiv.), EtOH (25 mL), dioxane (25 mL), 4M NaOH (5 mL) were added. The resulting solution was stirred in an oil bath at 80 °C for 4 h. The resulting mixture was concentrated under vacuum. The pH value of the solution was adjusted to 5-6 with HCl (2 mol/L). The solid was collected by filtration. This gave 1.1 g (80%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[14-oxa-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradec-1(9),2,5,7-tetraen-10-yl]benzoic acid as a white solid. LC-MS: (ES, m/z): M+H=626, R,T= 2.138 min.
4-(4-[[2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エン-1-イル]メチル]ピペラジン-1-イル)-N-[4-([[(2R)-1,4-ジオキサン-2-イル]メチル]アミノ)-3-ニトロベンゼンスルホニル]-2-[14-オキサ-2,4,10-トリアザトリシクロ[7.5.0.0^[3,7]]テトラデカ-1(9),2,5,7-テトラエン-10-イル]ベンズアミドの合成。40mLバイアル中へ、4-(4-[[2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エン-1-イル]メチル]ピペラジン-1-イル)-2-[14-オキサ-2,4,10-トリアザトリシクロ[7.5.0.0^[3,7]]テトラデカ-1(9),2,5,7-テトラエン-10-イル]安息香酸(150 mg、0.240 mmol、1当量)、DCM(3mL)、4-([[(2R)-1,4-ジオキサン-2-イル]メチル]アミノ)-3-ニトロベンゼン-1-スルホンアミド(76 mg、0.240 mmol、1.00当量)、EDCI(92 mg、0.480 mmol、2.00当量)、DMAP(117 mg、0.958 mmol、4.00当量)を入れた。得られる溶液を25℃で一晩撹拌した。得られる混合物を真空下で濃縮した。粗生成物を分取HPLCにより以下の条件で精製した(2#SHIMADZU(HPLC-01)):カラム、XBridge Prep C18 OBDカラム、5 um、19×150 mm;移動相、ACN及び水(0.05%NH3.H20)(20%相Bを1分で75%まで上昇させ、7分で95%まで上昇させ、95%で1分維持し、1分で20%まで低下させる);検出器、254/220 nm。これにより28 mg(12.63%)の4-(4-[[2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エン-1-イル]メチル]ピペラジン-1-イル)-N-[4-([[(2R)-1,4-ジオキサン-2-イル]メチル]アミノ)-3-ニトロベンゼンスルホニル]-2-[14-オキサ-2,4,10-トリアザトリシクロ[7.5.0.[3,7]]テトラデカ-1(9),2,5,7-テトラエン-10-イル]ベンズアミドが黄色固体として得られた。LC-MS: (ES, m/z): M+1=925, ee=100%、[a]=+7.4(C=0.106 g/100 mLのCH2Cl2、T=27℃)、R,T=3.425 min。逆相カラム(C18)により保持時間の測定を行った。Shimadzu LCMS 2020; 50×3.0 SUPELCO Ascentis Express C18、2.7um;溶離液A:水(0.05% TFA);溶離液B:アセトニトリル;7.0分で5%アセトニトリルから95%アセトニトリルまでの直線的グラジエント;オーブン温度40℃;流量:1.5 mL/分。1H NMR (300 MHz, DMSO-d6, ppm) δ 11.90 (s, 1H), 11.20 (s, 1H), 8.60 - 8.41 (m, 2H), 7.64 (d, J = 8.7 Hz, 1H), 7.47 (d, J = 8.7 Hz, 1H), 7.36 (d, J = 8.1 Hz, 2H), 7.20 (t, J = 2.9 Hz, 1H), 7.07 (d, J = 8.1 Hz, 2H), 6.90 (d, J = 12.1 Hz, 2H), 6.70 (d, J = 8.6 Hz, 2H), 6.19 - 6.06 (m, 1H), 4.20 (d, J = 6.5 Hz, 2H), 3.88 - 3.71 (m, 3H), 3.69 - 3.32 (m, 8H), 3.28 (s, 0H), 3.20 (s, 4H), 2.78 (s, 2H), 2.22 (d, J = 18.1 Hz, 6H), 1.98 (s, 4H), 1.51 - 1.34 (m, 2H), 0.95 (s, 6H). Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-N-[4-([[(2R)-1,4-dioxan-2-yl]methyl]amino)-3-nitrobenzenesulfonyl]-2-[14-oxa-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradec-1(9),2,5,7-tetraen-10-yl]benzamide. Into a 40 mL vial was placed 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[14-oxa-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradec-1(9),2,5,7-tetraen-10-yl]benzoic acid (150 mg, 0.240 mmol, 1 equiv.), DCM (3 mL), 4-([[(2R)-1,4-dioxan-2-yl]methyl]amino)-3-nitrobenzene-1-sulfonamide (76 mg, 0.240 mmol, 1.00 equiv.), EDCI (92 mg, 0.480 mmol, 2.00 equiv.), and DMAP (117 mg, 0.958 mmol, 4.00 equiv.). The resulting solution was stirred at 25° C. overnight. The resulting mixture was concentrated under vacuum. The crude product was purified by preparative HPLC with the following conditions (2#SHIMADZU (HPLC-01)): column, XBridge Prep C18 OBD column, 5 um, 19×150 mm; mobile phase, ACN and water (0.05% NH 3 .H 2 O) (20% phase B ramped to 75% in 1 min, ramped to 95% in 7 min, held at 95% for 1 min, ramped to 20% in 1 min); detector, 254/220 nm. This gave 28 mg (12.63%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-N-[4-([[(2R)-1,4-dioxan-2-yl]methyl]amino)-3-nitrobenzenesulfonyl]-2-[14-oxa-2,4,10-triazatricyclo[7.5.0.[3,7]]tetradec-1(9),2,5,7-tetraen-10-yl]benzamide as a yellow solid. LC-MS: (ES, m/z): M+1=925, ee=100%, [a]=+7.4 (C=0.106 g/100 mL of CH2Cl2 , T=27°C), R,T=3.425 min. Retention times were measured using a reversed phase column (C18). Shimadzu LCMS 2020; 50×3.0 SUPELCO Ascentis Express C18, 2.7um; Eluent A: water (0.05% TFA); Eluent B: acetonitrile; linear gradient from 5% acetonitrile to 95% acetonitrile in 7.0 min; oven temperature 40 °C; flow rate: 1.5 mL/min. 1H NMR (300 MHz, DMSO-d 6, ppm) δ 11.90 (s, 1H), 11.20 (s, 1H), 8.60 - 8.41 (m, 2H), 7.64 (d, J = 8.7 Hz, 1H), 7.47 (d, J = 8.7 Hz, 1H), 7.36 (d, J = 8.1 Hz, 2H), 7.20 (t, J = 2.9 Hz, 1H), 7.07 (d, J = 8.1 Hz, 2H), 6.90 (d, J = 12.1 Hz, 2H), 6.70 (d, J = 8.6 Hz, 2H), 6.19 - 6.06 (m, 1H), 4.20 (d, J = 6.5 Hz, 2H), 3.88 - 3.71 (m, 3H), 3.69 - 3.32 (m, 8H), 3.28 (s, 0H), 3.20 (s, 4H), 2.78 (s, 2H), 2.22 (d, J = 18.1 Hz, 6H), 1.98 (s, 4H), 1.51 - 1.34 (m, 2H), 0.95 (s, 6H).
[実施例9]
4-(4-[[2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エン-1-イル]メチル]ピペラジン-1-イル)-N-[4-([[(2S)-1,4-ジオキサン-2-イル]メチル]アミノ)-3-ニトロベンゼンスルホニル]-2-[14-オキサ-2,4,10-トリアザトリシクロ[7.5.0.0^[3,7]]テトラデカ-1(9),2,5,7-テトラエン-10-イル]ベンズアミドの調製
4-([[(2S)-1,4-ジオキサン-2-イル]メチル]アミノ)-3-ニトロベンゼン-1-スルホンアミドの合成。100mL丸底フラスコ中へ、4-フルオロ-3-ニトロベンゼン-1-スルホンアミド(1.43 g、0.007 mmol、1当量)、1-[(2S)-1,4-ジオキサン-2-イル]メタンアミン塩酸塩(1 g、6.510 mmol、1当量)、THF(30 mL)、Cs2CO3(8.48 g、0.026 mmol、4当量)を入れた。得られる溶液を油浴中で50℃で一晩撹拌した。固体をろ過によって回収した。固体を減圧下で乾燥器内で乾燥させた。これにより1.82 g(88.10%)の4-([[(2S)-1,4-ジオキサン-2-イル]メチル]アミノ)-3-ニトロベンゼン-1-スルホンアミドが黄色固体として得られた。LC-MS: (ES, m/z): M+1=318, R,T= 0.741分.ee=99%、[a]=-17.4(100 mlのDMSO中C=0.102 g、T=27℃)。
[Example 9]
Preparation of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-N-[4-([[(2S)-1,4-dioxan-2-yl]methyl]amino)-3-nitrobenzenesulfonyl]-2-[14-oxa-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradec-1(9),2,5,7-tetraen-10-yl]benzamide
Synthesis of 4-([[(2S)-1,4-dioxan-2-yl]methyl]amino)-3-nitrobenzene-1-sulfonamide. In a 100 mL round bottom flask were placed 4-fluoro-3-nitrobenzene-1-sulfonamide (1.43 g, 0.007 mmol, 1 equiv), 1-[(2S)-1,4-dioxan-2-yl] methanamine hydrochloride (1 g, 6.510 mmol, 1 equiv), THF (30 mL), and Cs2CO3 (8.48 g, 0.026 mmol, 4 equiv). The resulting solution was stirred overnight at 50° C. in an oil bath. The solid was collected by filtration. The solid was dried in an oven under reduced pressure. This gave 1.82 g (88.10%) of 4-([[(2S)-1,4-dioxan-2-yl]methyl]amino)-3-nitrobenzene-1-sulfonamide as a yellow solid. LC-MS: (ES, m/z): M+1=318, R,T= 0.741 min. ee=99%, [a]=-17.4 (C=0.102 g in 100 ml DMSO, T=27° C.).
4-(4-[[2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エン-1-イル]メチル]ピペラジン-1-イル)-N4-([[(2S)-1,4-ジオキサン-2-イル]メチル]アミノ)-3-ニトロベンゼンスルホニル]-2-[14-オキサ-2,4,10-トリアザトリシクロ[7.5.0.0^[3,7]]テトラデカ-1(9),2,5,7-テトラエン-10-イル]ベンズアミドの合成。40mLバイアル中へ、4-(4-[[2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エン-1-イル]メチル]ピペラジン-1-イル)-2-[14-オキサ-2,4,10-トリアザトリシクロ[7.5.0.0^[3,7]]テトラデカ-1(9),2,5,7-テトラエン-10-イル]安息香酸(150 mg、0.240 mmol、1当量)、DCM(3 mL)、4-([[(2S)-1,4-ジオキサン-2-イル]メチル]アミノ)-3-ニトロベンゼン-1-スルホンアミド(76 mg、0.240 mmol、1.00当量)、EDCI(92 mg、0.480 mmol、2.00当量)、DMAP(117 mg、0.958 mmol、4.00当量)を入れた。得られる溶液を25℃で一晩撹拌した。得られる混合物を真空下で濃縮した。粗生成物を分取HPLCにより以下の条件で精製した(2#SHIMADZU(HPLC-01)):カラム、XBridge Prep C18 OBDカラム、5 um、19×150 mm;移動相、ACN及び水(0.05%NH3.H2O)(20%相Bを1分で75%まで上昇させ、7分で95%まで上昇させ、95%で1分維持し、1分間で20%まで低下させる);検出器、254/220 nm。これにより29 mg(13.08%)の4-(4-[[2-(4-クロロフェニル)-4,4-ジメチルシクロヘキサ-1-エン-1-イル]メチル]ピペラジン-1-イル)-N-[4-([[(2S)-1,4-ジオキサン-2-イル]メチル]アミノ)-3-ニトロベンゼンスルホニル]-2-[14-オキサ-2,4,10-トリアザトリシクロ[7.5.0.0^[3,7]]テトラデカ-1(9),2,5,7-テトラエン-10-イル]ベンズアミドが黄色固体として得られた。LC-MS: (ES, m/z): M+1=925, R,T= 3.426分.ee=100%、[a]=-10.4(C=0.120 g/100 mLのCH2Cl2、T=27℃)。1H NMR (300 MHz, DMSO-d6, ppm) δ 11.90 (s, 1H), 11.20 (s, 1H), 8.60 - 8.41 (m, 2H), 7.64 (d, J = 8.7 Hz, 1H), 7.47 (d, J = 8.7 Hz, 1H), 7.36 (d, J = 8.1 Hz, 2H), 7.20 (t, J = 2.9 Hz, 1H), 7.07 (d, J = 8.1 Hz, 2H), 6.90 (d, J = 12.1 Hz, 2H), 6.70 (d, J = 8.6 Hz, 2H), 6.19 - 6.06 (m, 1H), 4.20 (d, J = 6.5 Hz, 2H), 3.88 - 3.71 (m, 3H), 3.69 - 3.32 (m, 8H), 3.28 (s, 0H), 3.20 (s, 4H), 2.78 (s, 2H), 2.22 (d, J = 18.1 Hz, 6H), 1.98 (s, 4H), 1.51 - 1.34 (m, 2H), 0.95 (s, 6H). Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-N4-([[(2S)-1,4-dioxan-2-yl]methyl]amino)-3-nitrobenzenesulfonyl]-2-[14-oxa-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradec-1(9),2,5,7-tetraen-10-yl]benzamide. Into a 40 mL vial was placed 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[14-oxa-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradec-1(9),2,5,7-tetraen-10-yl]benzoic acid (150 mg, 0.240 mmol, 1 equiv.), DCM (3 mL), 4-([[(2S)-1,4-dioxan-2-yl]methyl]amino)-3-nitrobenzene-1-sulfonamide (76 mg, 0.240 mmol, 1.00 equiv.), EDCI (92 mg, 0.480 mmol, 2.00 equiv.), and DMAP (117 mg, 0.958 mmol, 4.00 equiv.). The resulting solution was stirred at 25° C. overnight. The resulting mixture was concentrated under vacuum. The crude product was purified by preparative HPLC with the following conditions (2#SHIMADZU (HPLC-01)): column, XBridge Prep C18 OBD column, 5 um, 19×150 mm; mobile phase, ACN and water (0.05% NH 3 .H 2 O) (20% phase B ramped to 75% in 1 min, ramped to 95% in 7 min, held at 95% for 1 min, ramped to 20% in 1 min); detector, 254/220 nm. This gave 29 mg (13.08%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-N-[4-([[(2S)-1,4-dioxan-2-yl]methyl]amino)-3-nitrobenzenesulfonyl]-2-[14-oxa-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradec-1(9),2,5,7-tetraen-10-yl]benzamide as a yellow solid. LC-MS: (ES, m/z): M+1=925, R,T= 3.426 min. ee=100%, [a]=-10.4 (C=0.120 g/100 mL of CH2Cl2 , T=27°C). 1H NMR (300 MHz, DMSO-d 6, ppm) δ 11.90 (s, 1H), 11.20 (s, 1H), 8.60 - 8.41 (m, 2H), 7.64 (d, J = 8.7 Hz, 1H), 7.47 (d, J = 8.7 Hz, 1H), 7.36 (d, J = 8.1 Hz, 2H), 7.20 (t, J = 2.9 Hz, 1H), 7.07 (d, J = 8.1 Hz, 2H), 6.90 (d, J = 12.1 Hz, 2H), 6.70 (d, J = 8.6 Hz, 2H), 6.19 - 6.06 (m, 1H), 4.20 (d, J = 6.5 Hz, 2H), 3.88 - 3.71 (m, 3H), 3.69 - 3.32 (m, 8H), 3.28 (s, 0H), 3.20 (s, 4H), 2.78 (s, 2H), 2.22 (d, J = 18.1 Hz, 6H), 1.98 (s, 4H), 1.51 - 1.34 (m, 2H), 0.95 (s, 6H).
以下の化合物は上記スキーム及び実施例で開示されたものと実質的に同一の、同様の、又は類似の方法により調製されている: The following compounds have been prepared by methods substantially identical, similar, or analogous to those disclosed in the above schemes and examples:
[生物学的実施例1]
Bcl-2競合結合(蛍光偏光法)アッセイ
蛍光標識した23アミノ酸ペプチドBH3をCalBiochem(NLWAAQRYGRELRRMSDKFVD)から購入した。未結合フルオレセイン標識したBH3ペプチドは、励起光の偏光面の面に対してランダムな光を放出して、より低い偏光度(mP)の値をもたらす。ペプチドがBcl-2に結合した場合、複合体はより遅く回転し、放出光はより高いレベルの偏光を有することができ、より高いmP値をもたらす。この結合アッセイは96-ウェルプレートで実施し、各アッセイは、15及び30nMの標識ペプチド及び精製されたBcl-2タンパク質(R&D Systems, Incから購入)を含有した。アッセイ緩衝液は20mM Hepes(pH 7.0)、50mM KCl、5mM MgCl2、20mM Na2MoO4、0.1mg/mlのウシガンマグロブリン及び0.01% NP40を含有した。化合物をDMSO中で希釈し、20μM~2nMの濃度範囲で最終アッセイに加えた。室温で3時間インキュベーションした後、バックグランドを減算してBioTek Synergy IIにより偏光度(mP)の値を決定した。シグモイド用量反応曲線フィッティングを用いたPrismソフトウエアを使用してIC50を計算した。ABT-737を基準化合物として使用した。試験化合物の用量範囲内で行ったそのようなアッセイは、近似IC50値の決定を可能にした。予想されたように、本発明の化合物の阻害特性は構造的変化と共に変動するが、これらの薬剤により一般的に示された活性はIC50=0.1~1000nMの範囲内にあった。
Biological Example 1
Bcl-2 Competitive Binding (Fluorescence Polarization) Assay Fluorescently labeled 23 amino acid peptide BH3 was purchased from CalBiochem (NLWAAQRYGRELRRMSDKFVD). Unbound fluorescein labeled BH3 peptide emits random light relative to the plane of polarization of the excitation light, resulting in lower mP values. When the peptide binds to Bcl-2, the complex rotates slower and the emitted light can have a higher level of polarization, resulting in higher mP values. This binding assay was performed in a 96-well plate, with each assay containing 15 and 30 nM of labeled peptide and purified Bcl-2 protein (purchased from R&D Systems, Inc). The assay buffer contained 20 mM Hepes (pH 7.0), 50 mM KCl, 5 mM MgCl2, 20 mM Na2MoO4 , 0.1 mg/ml bovine gamma globulin, and 0.01% NP40. Compounds were diluted in DMSO and added to the final assay at a concentration range of 20 μM to 2 nM. After 3 hours of incubation at room temperature, the degree of polarization (mP) values were determined with a BioTek Synergy II with background subtraction. IC50s were calculated using Prism software with sigmoidal dose-response curve fitting. ABT-737 was used as a reference compound. Such assays, performed within a dose range of the test compounds, allowed for the determination of approximate IC50 values. As expected, the inhibitory properties of the compounds of the invention vary with structural changes, but the activity typically exhibited by these agents was in the range of IC50 = 0.1-1000 nM.
[生物学的実施例2]
BCL-2依存性急性リンパ芽球性白血病(ALL)細胞株RS4;11におけるin vitro抗増殖性アッセイ
細胞抗増殖をPerkinElmer ATPlite(商標)Luminescence Assay Systemでアッセイした。簡単に説明すると、Costar 96-ウェルプレートに、1つのウェル当たり約1×104個の細胞の密度で様々な試験癌細胞株を播種し、5% FBS又は10%正常ヒト血清(NHS)を加えた培地で異なる濃度の化合物と共に約72時間インキュベートした。次いで5mLの基質緩衝液を加えることにより1つの凍結乾燥された基質溶液のバイアルを再構成し、溶液が均質になるまで穏やかに撹拌した。約50μLの哺乳類細胞溶解溶液を、マイクロプレートの1つのウェル当たり100μLの細胞懸濁液に加え、プレートを約700rpmで、オービタルシェーカー内で約5分間振とうした。この手順を使用して細胞を溶解し、ATPを安定化させた。次に、50μLの基質溶液をウェルに加え、オービタルシェーカー内で、マイクロプレートを約700rpmで5分間振とうした。最後に、PerkinElmer TopCount(登録商標)マイクロプレートシンチレーションカウンターで発光を測定した。試験化合物の用量範囲内で行ったそのようなアッセイは、本発明の化合物の細胞抗抗増殖性のIC50の決定を可能にした。以下の表は本発明の特定の化合物のIC50値を列挙する。以下に示されているように、実施例3はNW-4-8(実施例2)並びにABT-199の両方よりも大幅に強力である。
[Biological Example 2]
In Vitro Antiproliferative Assay in BCL-2-Dependent Acute Lymphoblastic Leukemia (ALL) Cell Line RS4;11 Cellular antiproliferation was assayed with the PerkinElmer ATPlite™ Luminescence Assay System. Briefly, various test cancer cell lines were seeded at a density of approximately 1× 104 cells per well in Costar 96-well plates and incubated with different concentrations of compounds in medium supplemented with 5% FBS or 10% normal human serum (NHS) for approximately 72 hours. One lyophilized vial of substrate solution was then reconstituted by adding 5 mL of substrate buffer and gently agitated until the solution was homogenous. Approximately 50 μL of mammalian cell lysis solution was added to 100 μL of cell suspension per well of the microplate, and the plate was shaken at approximately 700 rpm in an orbital shaker for approximately 5 minutes. This procedure was used to lyse the cells and stabilize the ATP. Then, 50 μL of substrate solution was added to the wells, and the microplate was shaken at about 700 rpm for 5 minutes in an orbital shaker. Finally, luminescence was measured in a PerkinElmer TopCount® microplate scintillation counter. Such assays, performed within a range of doses of test compounds, allowed the determination of the IC 50 of the cellular anti-proliferative properties of the compounds of the present invention. The following table lists the IC 50 values of certain compounds of the present invention. As shown below, Example 3 is significantly more potent than both NW-4-8 (Example 2) as well as ABT-199.
以下の表は、本発明の特定の化合物についての別の研究のIC50値を列挙する。 The following table lists IC50 values from different studies for certain compounds of the present invention.
[生物学的実施例3]
小細胞肺癌(SCLC)細胞株におけるin vitro抗増殖性アッセイ
細胞抗増殖をPerkinElmer ATPlite(商標)Luminescence Assay Systemでアッセイした。簡単に説明すると、Costar 96-ウェルプレートに、1つのウェル当たり約1×104個の細胞の密度で様々な試験癌細胞株を播種し、5% FBSを加えた培地で異なる濃度の化合物と共に約72時間インキュベートした。次いで5mLの基質緩衝液を加えることにより1つの凍結乾燥基質溶液バイアルを再構成し、溶液が均質になるまで穏やかに撹拌した。約50μLの哺乳類細胞溶解溶液を、マイクロプレートの1つのウェル当たり100μLの細胞懸濁液に加え、オービタルシェーカー内で、約700rpmで約5分間プレートを振とうした。本手順を使用して細胞を溶解し、ATPを安定化させた。次に、50μLの基質溶液をウェルに加え、マイクロプレートを約700 rpmで、オービタルシェーカー内で5分間振とうした。最後に、PerkinElmer TopCount(登録商標)マイクロプレートシンチレーションカウンターで発光を測定した。試験化合物の用量範囲内で行ったそのようなアッセイは、本発明の化合物の細胞抗抗増殖性IC50の決定を可能にした。以下の表は本発明の特定の化合物についてのいくつかの癌細胞株(5%FBS)のIC50値を列挙する。
[Biological Example 3]
In Vitro Antiproliferative Assay in Small Cell Lung Cancer (SCLC) Cell Lines Cellular antiproliferation was assayed with the PerkinElmer ATPlite™ Luminescence Assay System. Briefly, various test cancer cell lines were seeded at a density of approximately 1× 104 cells per well in Costar 96-well plates and incubated with different concentrations of compounds in medium supplemented with 5% FBS for approximately 72 hours. One lyophilized substrate solution vial was then reconstituted by adding 5 mL of substrate buffer and gently agitated until the solution was homogenous. Approximately 50 μL of mammalian cell lysis solution was added to 100 μL of cell suspension per well of the microplate and the plate was shaken at approximately 700 rpm in an orbital shaker for approximately 5 minutes. This procedure was used to lyse the cells and stabilize the ATP. Then, 50 μL of substrate solution was added to the wells and the microplate was shaken at approximately 700 rpm in an orbital shaker for 5 minutes. Finally, luminescence was measured in a PerkinElmer TopCount® microplate scintillation counter. Such assays, performed within a range of doses of the test compound, allowed the determination of the cellular anti-proliferative IC50 of the compounds of the present invention. The following table lists the IC50 values of several cancer cell lines (5% FBS) for certain compounds of the present invention.
以下の表は、本発明の特定の化合物についてのいくつかの小細胞肺癌細胞株(5%FBS)のIC50値を列挙する。小細胞肺癌細胞株の標準的ケアであるシスプラチンをポジティブコントロール薬物として使用した。 The following table lists IC50 values for several small cell lung cancer cell lines (5% FBS) for certain compounds of the present invention. Cisplatin, the standard of care for small cell lung cancer cell lines, was used as a positive control drug.
[生物学的実施例4]
マウスPK研究
CD-1マウスにおいて静脈内及び経口投与により化合物の薬物動態を評価した。静脈内用量は頸静脈内の緩徐なボーラス投与として投与され、経口用量は経管栄養により投与された。静脈内投与のための配合は水中20% HPBCD中の5% DMSOであり、経口の配合は2.5% DMSO、10% EtOH、20% Cremphor EL、67.5% D5Wであった。静脈内の治療群についてのPKの時点は投与後5、15、30分、1、2、4、6、8、12、24時間であり、経口の治療群については、投与後15、30分、1、2、4、6、8、12、24時間であった。およそ0.03mLの血液を各時点で採取した。各試料の血液をEDTA-K2が入ったプラスチックマイクロ遠心管に移し、4℃の遠心分離機において4000gで5分の遠心分離により15分以内に血漿を採取した。血漿試料はポリプロピレンチューブ中に保存された。試料は分析の前に-75±15℃の冷凍庫内で保存された。血漿試料における化合物の濃度はLC-MS/MS法を使用して分析された。WinNonlin(Phoenix(商標)、6.1バージョン)又は他の同様のソフトウエアが薬物動態の計算に使用された。次の薬物動態パラメーターは、血漿濃度対時間のデータから可能である限り、計算された:静脈内投与: C0、CL、Vd、T1/2、AUCinf、AUClast、MRT、回帰の点の数;経口投与: Cmax、Tmax、T1/2、AUCinf、AUClast、F%、回帰の点の数。薬物動態データは、平均、標準偏差などの記述統計を使用して記載された。さらなる薬物動態又は統計分析は、貢献する科学者の裁量で行われ、データのまとめにおいて記録された。10mg/kgの経口投与のPK結果が以下の表に示されている。
Biological Example 4
Mouse PK studies
The pharmacokinetics of the compounds were evaluated in CD-1 mice by intravenous and oral administration. The intravenous dose was administered as a slow bolus in the jugular vein, and the oral dose was administered by gavage. The formulation for intravenous administration was 5% DMSO in 20% HPBCD in water, and the oral formulation was 2.5% DMSO, 10% EtOH, 20% Cremphor EL, 67.5% D5W. PK time points for the intravenous treatment group were 5, 15, 30 min, 1, 2, 4, 6, 8, 12, 24 h post-dose, and for the oral treatment group were 15, 30 min, 1, 2, 4, 6, 8, 12, 24 h post-dose. Approximately 0.03 mL of blood was collected at each time point. Blood for each sample was transferred to a plastic microcentrifuge tube containing EDTA-K2, and plasma was collected within 15 min by centrifugation at 4000 g for 5 min in a 4°C centrifuge. Plasma samples were stored in polypropylene tubes. Samples were stored in a freezer at -75±15°C prior to analysis. Compound concentrations in plasma samples were analyzed using LC-MS/MS methods. WinNonlin (Phoenix™, version 6.1) or other similar software was used for pharmacokinetic calculations. The following pharmacokinetic parameters were calculated, where possible, from plasma concentration versus time data: intravenous administration: C 0 , CL, V d , T 1/2 , AUC inf , AUC last , MRT, number of regression points; oral administration: C max , T max , T 1/2 , AUC inf , AUC last , F%, number of regression points. Pharmacokinetic data were described using descriptive statistics such as mean, standard deviation. Further pharmacokinetic or statistical analyses were performed at the discretion of the contributing scientist and were recorded in the data summary. PK results for oral administration of 10 mg/kg are shown in the table below.
比較目的のため、WO/2017/132474における特定の化合物10 mg/kgの経口投与のPK結果が、以下の表に示されている。 For comparative purposes, PK results for oral administration of 10 mg/kg of certain compounds in WO/2017/132474 are shown in the table below.
[生物学的実施例5]
in vivo異種移植片研究
実施例3の化合物が、BCL-2依存性急性リンパ芽球性白血病(ALL)RS4;11異種移植片モデルにおけるin vivo研究に対して選択される。CB.17SCIDマウスは、週齢6~8週で販売元から購入し、最低7日間順化させる。次いで癌細胞をヌードマウスに移植する。特定の腫瘍型に応じて、腫瘍は通常インプランテーションから約2週後に検出可能となる。腫瘍サイズが約100~200 mm3に到達した時点で、感知できるほどの腫瘍サイズ及び形状を有する動物を、1つのビヒクル対照群及び治療群を含む、各々8匹のマウスの群にランダムに割り当てる。投与は、各研究の目的及び長さに応じて変動させ、通常約3~4週間進行する。腫瘍サイズ及び体重を通常週3回測定する。腫瘍サイズの変化の決定に加えて、最後の腫瘍測定を使用して、腫瘍サイズ変化比(T/C値)、すなわち異種移植片腫瘍評価のために米国国立癌研究所(National Cancer Institute)が開発した標準的な測定基準を生成する。ほとんどの場合には、以下の式を使用して%T/C値を計算する: %T/C=100×ΔT/ΔC、ΔT>0の場合。しかし、腫瘍退縮が生じた場合(ΔT<0)、以下の式を使用する: %T/T0=100×ΔT/TO。<42%の値は有意と考えられる。
(付記)
(付記1)
式(A)の化合物
Q1は、7員ヘテロシクロアルキル、7員ヘテロシクロアルケニル、又は7員ヘテロアリールであり、
Q2はアリール又はヘテロアリールであり、
Q3は、シクロアルキル、シクロアルケニル、ヘテロシクロアルキル、ヘテロシクロアルケニル、アリール、又はヘテロアリールであり、
Q4は、
R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、及びR12の各々は、独立に、H、D、アルキル、アルケニル、アルキニル、シクロアルキル、シクロアルケニル、ヘテロシクロアルキル、ヘテロシクロアルケニル、アリール、ヘテロアリール、ハロ、ニトロ、オキソ、シアノ、ORa、SRa、アルキル-Ra、NH(CH2)pRa、C(O)Ra、S(O)Ra、SO2Ra、C(O)ORa、OC(O)Ra、NRbRc、P(O)RbRc、アルキル-P(O)RbRc、C(O)N(Rb)Rc、N(Rb)C(O)Rc、S(O)(=N(Rb))Rc、-N=S(O)RbRc、SO2N(Rb)Rc、又はN(Rb)SO2Rcであり、ここで前記シクロアルキル、シクロアルケニル、ヘテロシクロアルキル、ヘテロシクロアルケニル、アリール、ヘテロアリールは、場合により1つ以上のRdで置換されており、
Ra、Rb、Rc及びRdは、独立に、H、D、アルキル、アルケニル、アルキニル、ハロ、シアノ、アミン、ニトロ、ヒドロキシ、=O、C(O)NHOH、C(O)OH、C(O)NH2、アルコキシ、アルコキシアルキル、ハロアルキル、ヒドロキシアルキル、アミノアルキル、アルキルカルボニル、アルコキシカルボニル、アルキルカルボニルアミノ、アルキルアミノ、オキソ、ハロ-アルキルアミノ、シクロアルキル、シクロアルケニル、ヘテロシクロアルキル、ヘテロシクロアルケニル、アリール、又はヘテロアリールであり、ここで前記アルキル、シクロアルキル、シクロアルケニル、ヘテロシクロアルキル、ヘテロシクロアルケニル、アリール、ヘテロアリールは、場合により1つ以上のReで置換されており、
Reは、H、D、アルキル、アルケニル、アルキニル、ハロ、シアノ、アミン、ニトロ、ヒドロキシ、=O、C(O)NHOH、アルコキシ、アルコキシアルキル、ハロアルキル、ヒドロキシアルキル、アミノアルキル、アルキルカルボニル、アルコキシカルボニル、アルキルカルボニルアミノ、アルキルアミノ、オキソ、ハロ-アルキルアミノ、シクロアルキル、シクロアルケニル、ヘテロシクロアルキル、ヘテロシクロアルケニル、アリール、又はヘテロアリールであり、
Z1は、結合、(CH2)p、N(H)、O、S、C(O)、S(O2)、OC(O)、C(O)O、OSO2、S(O2)O、C(O)S、SC(O)、C(O)C(O)、C(O)N(H)、N(H)C(O)、S(O2)N(H)、N(H)S(O2)、OC(O)O、OC(O)S、OC(O)N(H)、N(H)C(O)O、N(H)C(O)S、N(H)C(O)N(H)、(CH2)pN(H)(CH2)q、(CH2)pN(H)C(O)(CH2)q、(CH2)pC(O)N(H)(CH2)q、OC(O)N(H)(CH2)p+1N(H)(CH2)q、二価アルケニル基、又は二価アルキニル基であり、
Lは、結合、アルキル、アルケニル、アルキニル、シクロアルキル、シクロアルケニル、ヘテロシクロアルキル、ヘテロシクロアルケニル、アリール、又はヘテロアリールであり、ここで前記アルキル、シクロアルキル、シクロアルケニル、ヘテロシクロアルキル、ヘテロシクロアルケニル、アリール、又はヘテロアリールは、場合により1つ以上のRdで置換されており、
Y、W、W1、及びW2の各々は、独立に、CH又はNであり、
W3はO又はN(Ra)であり、
VはN、C、又はCHであり、
R9基の2つは、それらが結合している原子と共に、場合によりシクロアルキル又はヘテロシクロアルキルを形成してもよく、ここでR9の前記シクロアルキル又はヘテロシクロアルキルは、場合により1つ以上のRdで置換されており、
R2基の2つは、それらが結合している原子と共に、場合によりシクロアルキル又はヘテロシクロアルキルを形成してもよく、ここでR2の前記シクロアルキル又はヘテロシクロアルキルは、場合により1つ以上のRdで置換されており、
R10基の2つは、それらが結合している原子と共に、場合によりシクロアルキル又はヘテロシクロアルキルを形成してもよく、ここでR10の前記シクロアルキル又はヘテロシクロアルキルは、場合により1つ以上のRdで置換されており、
R11及びR12基は、それらが結合している原子と共に、場合によりシクロアルキル又はヘテロシクロアルキルを形成してもよく、ここでR11又はR12の前記シクロアルキル又はヘテロシクロアルキルは、場合により1つ以上のRdで置換されており、
R10及びR2基は、それらが結合している原子と共に、場合によりシクロアルキル又はヘテロシクロアルキルを形成してもよく、ここでR10又はR2の前記シクロアルキル又はヘテロシクロアルキルは、場合により1つ以上のRdで置換されており、
R4及び-Z1-L-R6基は、それらが結合している原子と共に、場合によりシクロアルキル、シクロアルケニル、ヘテロシクロアルキル、ヘテロシクロアルケニル、アリール、又はヘテロアリールを形成してもよく、ここでR4の前記シクロアルキル、シクロアルケニル、ヘテロシクロアルキル、ヘテロシクロアルケニル、アリール、又はヘテロアリールは、場合により1つ以上のRdで置換されており、
Rb及びRc基は、それらが結合している原子と共に、場合によりシクロアルキル、又はヘテロシクロアルキルを形成してもよく、ここでRb及びRcの前記シクロアルキル又はヘテロシクロアルキルは、場合により1つ以上のReで置換されており、
Rd基の2つは、それらが結合している原子と共に、場合によりシクロアルキル、又はヘテロシクロアルキルを形成してもよく、ここでRdの前記シクロアルキル又はヘテロシクロアルキルは、場合により1つ以上のReで置換されており、
Re基の2つは、それらが結合している原子と共に、場合によりシクロアルキル又はヘテロシクロアルキルを形成してもよく、ここでReの前記シクロアルキル又はヘテロシクロアルキルは、場合によりH、D、アルキル、アルケニル、アルキニル、ハロ、シアノ、アミン、ニトロ、ヒドロキシ、C(O)NHOH、アルコキシ、アルコキシアルキル、ハロアルキル、ヒドロキシアルキル、アミノアルキル、アルキルカルボニル、アルコキシカルボニル、アルキルカルボニルアミノ、アルキルアミノ、オキソ、ハロ-アルキルアミノ、シクロアルキル、シクロアルケニル、ヘテロシクロアルキル、ヘテロシクロアルケニル、アリール、又はヘテロアリールから選択される1つ以上の基で置換されており、
j及びkの各々は、独立に、0、1、2、3、4、5、6、7、又は8であり、
m、n、p、q、及びrの各々は、独立に、0、1、2、3、又は4である)
若しくはそのN-酸化物、又は前記式(A)の化合物若しくはそのN-酸化物の薬学的に許容可能な塩、溶媒和物、多形、互変異性体、立体異性体、同位体形態、若しくはプロドラッグ。
(付記2)
式(B)により表され:
Z2は、-O-、-CH2-、-C(O)-、-N(Ra)-、-S-、-S(O)-、-S(O2)-、-S(O)(=N(Ra))-、-P(O)(Ra)-であり、Z2のRaは、独立に、H、D、C1~C6アルキル、C2~C6アルケニル、C1~C6アルキルカルボニル、C1~C6アルコキシカルボニル、C3~C6シクロアルキル、5~8員単環式ヘテロシクロアルキル、C6~C14アリール、又は5~8員単環式ヘテロアリールであり、ここで前記C1~C6アルキル、C3~C6シクロアルキル、5~8員単環式ヘテロシクロアルキル、C6~C14アリール、5~8員単環式ヘテロアリールは、場合により1つ以上のReで置換されており、
Aは、-(CR2R2)r-又は-O-であり、rは、0、1、2、又は3であり、
各R2は、独立に、H、-(C1~C4)アルコキシ、場合により-(C1~C4)アルコキシで置換されている-(C1~C4)アルキルであるか、又は
R2基の2つは、それらが結合している同じ炭素原子と共に、-(C3~C6)シクロアルキル若しくは4~6員複素環式環を形成し、ここで前記-(C3~C6)シクロアルキル又は4~6員複素環式環は、場合により-(C1~C4)アルキル、-(C1~C4)ハロアルキル又はオキセタニルから選択される1つ以上の基で置換されている、
付記1に記載の化合物若しくはそのN-酸化物、又はその薬学的に許容可能な塩、溶媒和物、多形、互変異性体、立体異性体、同位体形態、若しくはプロドラッグ。
(付記3)
式(C)により表され:
付記2に記載の化合物若しくはそのN-酸化物、又はその薬学的に許容可能な塩、溶媒和物、多形、互変異性体、立体異性体、同位体形態、若しくはプロドラッグ。
(付記4)
式(D)により表され:
R5は、独立に、ニトロ、ハロ、又は-SO2Raであり、R5のRaは、-(C1~C4)アルキル又は-(C1~C4)ハロアルキルであり、
Z1は、結合、NH、N(H)(CH2)q、O、S、又は-(C1~C4)アルキレンであり、qは、1、2、又は3であり、
Lは、非存在、又は場合により-(C3~C6)シクロアルキルで置換されている-(C1~C4)アルキレンであり、
R6は、H、D、-N(CH3)-(C1~C4)アルキレン-P(O)((C1~C4)アルコキシ)2、-P(O)(N(CH3)2)(OEt)、-P(O)(O-(C1~C4)アルキレン-O-CO-(C1~C4)アルキル)2、-(C3~C6)シクロアルキル、フェニル、5~7員ヘテロシクリル、8~10員二環式環であり、ここで前記-(C3~C6)シクロアルキル、フェニル、5~7員ヘテロシクリル、又は7~10員二環式環は、場合によりハロ、-OH、=O、-CN、-COOH、-NH2、-N(CH3)2、-NS(=O)(CH3)2、-SO2(C1~C4)アルキル、-(C1~C4)アルキル、-(C1~C4)アルコキシ、-(C1~C4)ハロアルコキシ、シクロプロピル、4~6員ヘテロシクリル、-CH2P(O)(OH)2、-CH2P(O)((C1~C4)アルコキシ)2、-P(O)((C1~C4)アルキル)2、又は-N=S(O)((C1~C4)アルキル)2から選択される1つ以上の基で置換されている、
付記3に記載の化合物若しくはそのN-酸化物、又はその薬学的に許容可能な塩、溶媒和物、多形、互変異性体、立体異性体、同位体形態、若しくはプロドラッグ。
(付記5)
R9は、独立に、D、ハロ、-OH、CN、-NH2、=O、-(C1~C4)アルキル、-(C1~C4)アルコキシ、-(C1~C4)ハロアルキル、-(C1~C4)ヒドロキシアルキル、-(C3~C6)シクロアルキル、又は1,3-ジチオラニルであり、kが0、1、2、3、又は4である、付記4に記載の化合物若しくはそのN-酸化物、又はその薬学的に許容可能な塩、溶媒和物、多形、互変異性体、立体異性体、同位体形態、若しくはプロドラッグ。
(付記6)
Aは-CH2-又は-O-である、付記4又は5に記載の化合物若しくはそのN-酸化物、又はその薬学的に許容可能な塩、溶媒和物、多形、互変異性体、立体異性体、同位体形態、若しくはプロドラッグ。
(付記7)
各R2は独立に-CH3であり、nは0又は2である、付記4から6のいずれか一項に記載の化合物若しくはそのN-酸化物、又はその薬学的に許容可能な塩、溶媒和物、多形、互変異性体、立体異性体、同位体形態、若しくはプロドラッグ。
(付記8)
Z2は-O-である、付記4から7のいずれか一項に記載の化合物若しくはそのN-酸化物、又はその薬学的に許容可能な塩、溶媒和物、多形、互変異性体、立体異性体、同位体形態、若しくはプロドラッグ。
(付記9)
R1はClである、付記4から8のいずれか一項に記載の化合物若しくはそのN-酸化物、又はその薬学的に許容可能な塩、溶媒和物、多形、互変異性体、立体異性体、同位体形態、若しくはプロドラッグ。
(付記10)
R5はニトロである、付記4から9のいずれか一項に記載の化合物若しくはそのN-酸化物、又はその薬学的に許容可能な塩、溶媒和物、多形、互変異性体、立体異性体、同位体形態、若しくはプロドラッグ。
(付記11)
Z1は、非存在、NH又はOである、付記4から10のいずれか一項に記載の化合物若しくはそのN-酸化物、又はその薬学的に許容可能な塩、溶媒和物、多形、互変異性体、立体異性体、同位体形態、若しくはプロドラッグ。
(付記12)
Z2は、-O-、-CH2-、-C(O)-、-NH-、-N-(オキセタニル)-、-S-、-S(O)-、-S(O2)-、-S(O)(=NH)-、-S(O)(=NCH3)-、又は-P(O)(CH3)-である、付記4から11のいずれか一項に記載の化合物若しくはそのN-酸化物、又はその薬学的に許容可能な塩、溶媒和物、多形、互変異性体、立体異性体、同位体形態、若しくはプロドラッグ。
(付記13)
R6は、H、D、-(C3~C6)シクロアルキル、フェニル、テトラヒドロ-2H-ピラニル、又は1,4-ジオキサニルであり、ここで前記-(C3~C6)シクロアルキル、フェニル、テトラヒドロ-2H-ピラニル又は1,4-ジオキサニルは、場合によりハロゲン、-OH、=O、-(C1~C4)アルキル、又は-(C1~C4)アルコキシから選択される1又は2つの基で置換されている、付記4から12のいずれか一項に記載の化合物若しくはそのN-酸化物、又はその薬学的に許容可能な塩、溶媒和物、多形、互変異性体、立体異性体、同位体形態、若しくはプロドラッグ。
(付記14)
R6はテトラヒドロ-2H-ピラニル又は1,4-ジオキサニルであり、ここで前記テトラヒドロ-2H-ピラニル又は1,4-ジオキサニルは、場合によりハロゲンから選択される1又は2つの基で置換されている、付記4から13のいずれか一項に記載の化合物若しくはそのN-酸化物、又はその薬学的に許容可能な塩、溶媒和物、多形、互変異性体、立体異性体、同位体形態、若しくはプロドラッグ。
(付記15)
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
(R)-N-((4-(((1,4-ジオキサン-2-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
(S)-N-((4-(((1,4-ジオキサン-2-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
(S)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(4-メチル-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
N-((4-((((S)-1,4-ジオキサン-2-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-((S)-4-メチル-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
N-((4-((((R)-1,4-ジオキサン-2-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-((S)-4-メチル-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
(R)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(4-メチル-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
N-((4-((((S)-1,4-ジオキサン-2-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-((R)-4-メチル-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
N-((4-((((R)-1,4-ジオキサン-2-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-((R)-4-メチル-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(4,4-ジフルオロ-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
(R)-N-((4-(((1,4-ジオキサン-2-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(4,4-ジフルオロ-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
(S)-N-((4-(((1,4-ジオキサン-2-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(4,4-ジフルオロ-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-(((4-フルオロテトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミド、
(S)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-(((2-フルオロ-1,4-ジオキサン-2-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミド、
(R)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-(((2-フルオロ-1,4-ジオキサン-2-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミド、
(S)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-N-((4-(((4-フルオロテトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-2-(4-メチル-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-N-((4-((((R)-2-フルオロ-1,4-ジオキサン-2-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-2-((S)-4-メチル-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-N-((4-((((S)-2-フルオロ-1,4-ジオキサン-2-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-2-((S)-4-メチル-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
(R)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-N-((4-(((4-フルオロテトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-2-(4-メチル-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-N-((4-((((R)-2-フルオロ-1,4-ジオキサン-2-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-2-((R)-4-メチル-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-N-((4-((((S)-2-フルオロ-1,4-ジオキサン-2-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-2-((R)-4-メチル-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(4,4-ジフルオロ-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-(((4-フルオロテトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミド、
(S)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(4,4-ジフルオロ-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-(((2-フルオロ-1,4-ジオキサン-2-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミド、又は
(R)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(4,4-ジフルオロ-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-(((2-フルオロ-1,4-ジオキサン-2-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミド
である、付記1に記載の化合物若しくはそのN-酸化物、又はその薬学的に許容可能な塩、溶媒和物、多形、互変異性体、立体異性体、同位体形態、若しくはプロドラッグ。
(付記16)
付記1に記載の式(A)の化合物若しくはそのN-酸化物、又は前記式(A)の化合物若しくはそのN-酸化物の薬学的に許容可能な塩、溶媒和物、多形、互変異性体、立体異性体、同位体形態、若しくはプロドラッグ、及び薬学的に許容可能な希釈剤又は担体を含む医薬組成物。
(付記17)
新生物疾患、自己免疫疾患、又は神経変性疾患を治療する方法であって、それを必要とする対象に、有効量の付記1に記載の式(A)の化合物若しくはそのN-酸化物、又は前記式(A)の化合物若しくはそのN-酸化物の薬学的に許容可能な塩、溶媒和物、多形、互変異性体、立体異性体、同位体形態、若しくはプロドラッグを投与するステップを含む、方法。
(付記18)
新生物疾患、自己免疫疾患、又は神経変性疾患は、異常な(例えば、向上した、又は増加した)Bcl-2活性によって特徴づけられ、例えば、血液悪性腫瘍/癌、I型糖尿病、又は統合失調症である、付記16に記載の方法。
(付記19)
新生物疾患は、骨髄腫、多発性骨髄腫、リンパ腫、濾胞性リンパ腫(FL)、非ホジキンリンパ腫、白血病、急性白血病、急性リンパ芽球性白血病(ALL)(例えば、BCL-2依存性ALL及び小児ALL)、慢性リンパ芽球性白血病(CLL)(例えば、再発性/不応性CLL、del(17p)CLL)、慢性骨髄性白血病(CML)(例えば、急性転化CML)、マントル細胞リンパ腫(MCL)、びまん性大細胞型B細胞リンパ腫、肺癌、例えば、小細胞肺癌(SCLC)、黒色腫、乳癌、又は前立腺癌(それらの薬物耐性癌を含む)である、付記16に記載の方法。
(付記20)
新生物疾患を治療するのに有効な1つ以上のさらなる治療、例えば、手術、放射線療法、化学療法剤(例えば、ベンダムスチン、NL-101、シスプラチン、カルボプラチン、エトポシド、トポテカン)、標的療法(例えば、リツキシマブ、イブルチニブ、ACP-196、イデラリシブ);抗体薬物コンジュゲート又はADC(例えば、ブレンツキシマブベドチン)、免疫療法(例えば、ペムブロリズマブ、ニボルマブ、アテゾリズマブ、デュルバルマブ、アベルマブ)、又はCAR-T療法(例えば、チサゲンレクルユーセル、アキシカブタゲンシロロイセル)を投与するステップをさらに含む、付記16から19のいずれか一項に記載の方法。
Biological Example 5
In vivo xenograft studies The compound of Example 3 is selected for in vivo studies in the BCL-2-dependent acute lymphoblastic leukemia (ALL) RS4;11 xenograft model. CB.17 SCID mice are purchased from a commercial source at 6-8 weeks of age and allowed to acclimate for a minimum of 7 days. Cancer cells are then implanted into nude mice. Depending on the specific tumor type, tumors are usually detectable approximately 2 weeks after implantation. When tumor sizes reach approximately 100-200 mm3 , animals with appreciable tumor size and shape are randomly assigned to groups of 8 mice each, including one vehicle control group and one treatment group. Dosing varies depending on the purpose and length of each study, and usually proceeds for approximately 3-4 weeks. Tumor size and body weight are usually measured 3 times a week. In addition to determining the change in tumor size, the final tumor measurements are used to generate tumor size change ratios (T/C values), a standard metric developed by the National Cancer Institute for xenograft tumor evaluation. In most cases, the following formula is used to calculate %T/C values: %T/C=100×ΔT/ΔC, if ΔT>0. However, if tumor regression occurs (ΔT<0), the following formula is used: %T/T0=100×ΔT/TO. Values <42% are considered significant.
(Additional Note)
(Appendix 1)
Compound of formula (A)
Q1 is a 7-membered heterocycloalkyl, a 7-membered heterocycloalkenyl, or a 7-membered heteroaryl;
Q2 is aryl or heteroaryl;
Q3 is cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl;
Q4 is,
R1 , R2 , R3 , R4 , R5 , R6 , R7 , R8, R9 , R10 , R11 , and R12 are each independently selected from H, D, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, halo, nitro, oxo, cyano, ORa , SRa , alkyl- Ra , NH ( CH2 ) pRa , C(O) Ra , S(O) Ra , SO2Ra , C(O) ORa , OC (O) Ra , NRbRc , P(O) RbRc , alkyl-P(O) RbRc , C(O) N ( Rb ) Rc , N( Rb )C(O) Rc , S(O)(=N( Rb ) )) Rc , -N=S(O )RbRc, SO2N(Rb)Rc, or N(Rb)SO2Rc , wherein said cycloalkyl , cycloalkenyl , heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl are optionally substituted with one or more Rd ;
R a , R b , R c and R d are independently H, D, alkyl, alkenyl, alkynyl, halo, cyano, amine, nitro, hydroxy, =O, C(O)NHOH, C(O)OH, C(O)NH 2 , alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, halo-alkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl, wherein said alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl is optionally substituted with one or more Re ;
R e is H, D, alkyl, alkenyl, alkynyl, halo, cyano, amine, nitro, hydroxy, =O, C(O)NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, halo-alkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl;
Z1 is a bond, ( CH2 ) p , N(H), O, S, C(O), S( O2 ), OC(O), C(O)O, OSO2 , S( O2 )O, C(O)S, SC(O), C(O)C(O), C(O)N(H), N(H)C(O), S( O2 )N(H), N(H)S( O2 ), OC(O)O, OC(O)S, OC(O)N(H), N(H)C(O)O, N(H)C(O)S, N(H)C(O)N(H), ( CH2 ) pN (H)( CH2 ) q , ( CH2 ) pN (H)C(O)( CH2 ) q , ( CH2 ) pC (O)N(H)( CH2 ) q , OC(O)N(H)( CH2 ) p+1N (H)( CH2 ) q , a divalent alkenyl group, or a divalent alkynyl group;
L is a bond, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl, wherein said alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl is optionally substituted with one or more Rd ;
Each of Y, W, W1 , and W2 is independently CH or N;
W3 is O or N(R a );
V is N, C, or CH;
Two of the R 9 groups together with the atom to which they are attached may optionally form a cycloalkyl or heterocycloalkyl, where the cycloalkyl or heterocycloalkyl of R 9 is optionally substituted with one or more R d ;
Two of the R2 groups together with the atom to which they are attached may optionally form a cycloalkyl or heterocycloalkyl, where said cycloalkyl or heterocycloalkyl of R2 is optionally substituted with one or more Rd ;
Two of the R 10 groups together with the atom to which they are attached may optionally form a cycloalkyl or heterocycloalkyl, where the cycloalkyl or heterocycloalkyl of R 10 is optionally substituted with one or more R d ;
The R 11 and R 12 groups together with the atom to which they are attached may optionally form a cycloalkyl or heterocycloalkyl, wherein said cycloalkyl or heterocycloalkyl of R 11 or R 12 is optionally substituted with one or more R d ;
The R 10 and R 2 groups together with the atom to which they are attached may optionally form a cycloalkyl or heterocycloalkyl, wherein said cycloalkyl or heterocycloalkyl of R 10 or R 2 is optionally substituted with one or more R d ;
R4 and -Z1 - LR6 groups together with the atom to which they are attached may optionally form a cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl, wherein the cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl of R4 is optionally substituted with one or more Rd ;
The R b and R c groups together with the atom to which they are attached may optionally form a cycloalkyl, or heterocycloalkyl, where the cycloalkyl or heterocycloalkyl of R b and R c is optionally substituted with one or more Re ;
Two of the R d groups together with the atom to which they are attached may optionally form a cycloalkyl, or heterocycloalkyl, where the cycloalkyl or heterocycloalkyl of R d is optionally substituted with one or more Re ;
Two of the R e groups together with the atom to which they are attached may optionally form a cycloalkyl or heterocycloalkyl, where said cycloalkyl or heterocycloalkyl of R e is optionally substituted with one or more groups selected from H, D, alkyl, alkenyl, alkynyl, halo, cyano, amine, nitro, hydroxy, C(O)NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, halo-alkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl;
Each of j and k is independently 0, 1, 2, 3, 4, 5, 6, 7, or 8;
Each of m, n, p, q, and r is independently 0, 1, 2, 3, or 4.
or an N-oxide thereof, or a pharma- ceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form, or prodrug of said compound of formula (A) or an N-oxide thereof.
(Appendix 2)
Represented by formula (B):
Z2 is -O-, -CH2- , -C(O)-, -N(R a )-, -S-, -S(O)-, -S( O2 )-, -S(O)(=N(R a ))-, -P(O)(R a )-, R a of Z2 is independently H, D, C1 - C6 alkyl, C2- C6 alkenyl, C1 - C6 alkylcarbonyl, C1 - C6 alkoxycarbonyl, C3 - C6 cycloalkyl, 5-8 membered monocyclic heterocycloalkyl, C6 - C14 aryl, or 5-8 membered monocyclic heteroaryl, wherein said C1 - C6 alkyl, C3 - C6 cycloalkyl, 5-8 membered monocyclic heterocycloalkyl, C6 - C14 aryl, 5-8 membered monocyclic heteroaryl are optionally substituted with one or more Re ;
A is -( CR2R2 ) r- or -O-, where r is 0, 1, 2 , or 3;
each R2 is independently H, -( C1 - C4 )alkoxy, -( C1 - C4 )alkyl optionally substituted with -( C1 - C4 )alkoxy;
two of the R2 groups together with the same carbon atom to which they are attached form a -( C3 - C6 )cycloalkyl or a 4- to 6-membered heterocyclic ring, wherein said -( C3 - C6 )cycloalkyl or 4- to 6-membered heterocyclic ring is optionally substituted with one or more groups selected from -( C1 - C4 )alkyl, -( C1 - C4 )haloalkyl or oxetanyl;
A compound according to Appendix 1, or an N-oxide thereof, or a pharma- ceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form, or prodrug thereof.
(Appendix 3)
Represented by formula (C):
A compound according to Appendix 2, or an N-oxide thereof, or a pharma- ceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form, or prodrug thereof.
(Appendix 4)
Represented by formula (D):
R5 is independently nitro, halo, or -SO2R a , where R a of R5 is -( C1 - C4 )alkyl or -( C1 - C4 )haloalkyl;
Z 1 is a bond, NH, N(H)(CH 2 ) q , O, S, or -(C 1 -C 4 )alkylene, where q is 1, 2, or 3;
L is absent or -(C 1 -C 4 )alkylene optionally substituted with -(C 3 -C 6 )cycloalkyl;
R 6 is H, D, -N(CH 3 )-(C 1 -C 4 )alkylene-P(O)((C 1 -C 4 )alkoxy) 2 , -P(O)(N(CH 3 ) 2 )(OEt), -P(O)(O-(C 1 -C 4 )alkylene-O-CO-(C 1 -C 4 )alkyl) 2 , -(C 3 -C 6 )cycloalkyl, phenyl, 5- to 7-membered heterocyclyl, 8- to 10-membered bicyclic ring, wherein said -(C 3 -C 6 )cycloalkyl, phenyl, 5- to 7-membered heterocyclyl, or 7- to 10-membered bicyclic ring is optionally selected from halo, -OH, ═O, -CN, -COOH, -NH 2 , -N(CH 3 ) 2 , -NS(═O)(CH 3 ) 2 , -SO 2 (C 1 - C4 )alkyl, -( C1 - C4 )alkyl, -( C1 - C4 )alkoxy, -( C1 - C4 )haloalkoxy, cyclopropyl, 4- to 6-membered heterocyclyl, -CH2P (O)(OH) 2 , -CH2P (O)(( C1 - C4 )alkoxy) 2 , -P(O)(( C1 - C4 )alkyl) 2 , or -N=S(O)(( C1 - C4 )alkyl) 2 ;
A compound according to Appendix 3, or an N-oxide thereof, or a pharma- ceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form, or prodrug thereof.
(Appendix 5)
R 9 is independently D, halo, -OH, CN, -NH 2 , =O, -(C 1 -C 4 )alkyl, -(C 1 -C 4 )alkoxy, -(C 1 -C 4 )haloalkyl, -(C 1 -C 4 )hydroxyalkyl, -(C 3 -C 6 )cycloalkyl, or 1,3-dithiolanyl; and k is 0, 1, 2, 3, or 4; or a compound according to Appendix 4, or an N-oxide thereof, or a pharma- ceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form, or prodrug thereof.
(Appendix 6)
A compound according to claim 4 or 5, or an N-oxide thereof, or a pharma- ceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form, or prodrug thereof, wherein A is -CH2- or -O-.
(Appendix 7)
The compound of any one of claims 4 to 6, wherein each R2 is independently -CH3 and n is 0 or 2; or an N-oxide thereof; or a pharma- ceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form, or prodrug thereof.
(Appendix 8)
The compound of any one of claims 4 to 7, or an N-oxide thereof, or a pharma- ceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form, or prodrug thereof, wherein Z2 is -O-.
(Appendix 9)
The compound of any one of claims 4 to 8, or an N-oxide thereof, or a pharma- ceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form, or prodrug thereof, wherein R1 is Cl.
(Appendix 10)
The compound of any one of claims 4 to 9, or an N-oxide thereof, or a pharma- ceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form, or prodrug thereof, wherein R5 is nitro.
(Appendix 11)
11. The compound of any one of claims 4 to 10, wherein Z 1 is absent, NH or O; or an N-oxide thereof; or a pharma- ceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form, or prodrug thereof.
(Appendix 12)
A compound according to any one of Appendices 4 to 11, or an N-oxide thereof, or a pharma- ceutically acceptable salt, solvate , polymorph, tautomer, stereoisomer, isotopic form, or prodrug thereof, wherein Z2 is -O-, -CH2- , -C(O)-, -NH-, -N-( oxetanyl )-, -S-, -S(O)-, -S(O2)-, -S(O)(=NH)-, -S(O)(= NCH3 )-, or -P(O)(CH3)-.
(Appendix 13)
A compound according to any one of claims 4 to 12, or an N-oxide thereof , or a pharma- ceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form, or prodrug thereof, wherein R6 is H, D, -( C3 - C6 )cycloalkyl, phenyl, tetrahydro-2H-pyranyl, or 1,4-dioxanyl, wherein said -( C3 - C6 )cycloalkyl, phenyl, tetrahydro- 2H -pyranyl, or 1,4 -dioxanyl is optionally substituted with one or two groups selected from halogen, -OH, =O, -(C1-C4)alkyl, or -(C1-C4)alkoxy.
(Appendix 14)
or an N-oxide thereof; or a pharma- ceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form, or prodrug thereof; or the compound according to any one of claims 4 to 13, wherein R6 is tetrahydro-2H-pyranyl or 1,4-dioxanyl, wherein said tetrahydro-2H-pyranyl or 1,4-dioxanyl is optionally substituted with one or two groups selected from halogen.
(Appendix 15)
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
(R)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
(S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
(S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
N-((4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-((S)-4-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
N-((4-((((R)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-((S)-4-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
(R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
N-((4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-((R)-4-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
N-((4-((((R)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-((R)-4-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4,4-difluoro-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
(R)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4,4-difluoro-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
(S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4,4-difluoro-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,
(S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((2-fluoro-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,
(R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((2-fluoro-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,
(S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(4-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((R)-2-fluoro-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((S)-4-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((S)-2-fluoro-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((S)-4-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
(R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(4-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((R)-2-fluoro-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((R)-4-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((S)-2-fluoro-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((R)-4-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4,4-difluoro-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,
(S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4,4-difluoro-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((2-fluoro-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide, or
2. The compound of claim 1, which is (R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4,4-difluoro-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((2-fluoro-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide, or an N-oxide thereof, or a pharma- ceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form, or prodrug thereof.
(Appendix 16)
A pharmaceutical composition comprising a compound of formula (A) as defined in Appendix 1 or an N-oxide thereof, or a pharma- ceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form, or prodrug of said compound of formula (A) or an N-oxide thereof, and a pharma- ceutically acceptable diluent or carrier.
(Appendix 17)
1. A method of treating a neoplastic disease, an autoimmune disease, or a neurodegenerative disease, comprising administering to a subject in need thereof an effective amount of a compound of formula (A) as described in Appendix 1 or an N-oxide thereof, or a pharma- ceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form, or prodrug of said compound of formula (A) or an N-oxide thereof.
(Appendix 18)
The method of claim 16, wherein the neoplastic disease, autoimmune disease, or neurodegenerative disease is characterized by aberrant (e.g., improved or increased) Bcl-2 activity, e.g., hematological malignancies/cancer, type I diabetes, or schizophrenia.
(Appendix 19)
The method of claim 16, wherein the neoplastic disease is myeloma, multiple myeloma, lymphoma, follicular lymphoma (FL), non-Hodgkin's lymphoma, leukemia, acute leukemia, acute lymphoblastic leukemia (ALL) (e.g., BCL-2 dependent ALL and childhood ALL), chronic lymphoblastic leukemia (CLL) (e.g., relapsed/refractory CLL, del(17p)CLL), chronic myeloid leukemia (CML) (e.g., blast crisis CML), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma, lung cancer, e.g., small cell lung cancer (SCLC), melanoma, breast cancer, or prostate cancer (including drug resistant cancers thereof).
(Appendix 20)
The method of any one of claims 16 to 19, further comprising administering one or more additional therapies effective to treat the neoplastic disease, such as surgery, radiation therapy, a chemotherapeutic agent (e.g., bendamustine, NL-101, cisplatin, carboplatin, etoposide, topotecan), a targeted therapy (e.g., rituximab, ibrutinib, ACP-196, idelalisib); an antibody drug conjugate or ADC (e.g., brentuximab vedotin), an immunotherapy (e.g., pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab), or a CAR-T therapy (e.g., tisagenlecleucel, axicabtageneciloleucel).
Claims (36)
Q1は、7員ヘテロシクロアルキル、7員ヘテロシクロアルケニル、又は7員ヘテロアリールであり、
Q2はアリール又はヘテロアリールであり、
Q3は、シクロアルキル、シクロアルケニル、ヘテロシクロアルキル、ヘテロシクロアルケニル、アリール、又はヘテロアリールであり、
Q4は、
R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、及びR12の各々は、独立に、H、D、アルキル、アルケニル、アルキニル、シクロアルキル、シクロアルケニル、ヘテロシクロアルキル、ヘテロシクロアルケニル、アリール、ヘテロアリール、ハロ、ニトロ、=O、シアノ、ORa、SRa、アルキル-Ra、NH(CH2)pRa、C(O)Ra、S(O)Ra、SO2Ra、C(O)ORa、OC(O)Ra、NRbRc、P(O)RbRc、アルキル-P(O)RbRc、C(O)N(Rb)Rc、N(Rb)C(O)Rc、S(O)(=N(Rb))Rc、-N=S(O)RbRc、SO2N(Rb)Rc、又はN(Rb)SO2Rcであり、ここで前記シクロアルキル、シクロアルケニル、ヘテロシクロアルキル、ヘテロシクロアルケニル、アリール、ヘテロアリールは、場合により1つ以上のRdで置換されており、
Ra、Rb、Rc及びRdは、独立に、H、D、アルキル、アルケニル、アルキニル、ハロ、シアノ、アミン、ニトロ、ヒドロキシ、C(O)NHOH、C(O)OH、C(O)NH2、アルコキシ、アルコキシアルキル、ハロアルキル、ヒドロキシアルキル、アミノアルキル、アルキルカルボニル、アルコキシカルボニル、アルキルカルボニルアミノ、アルキルアミノ、=O、ハロ-アルキルアミノ、シクロアルキル、シクロアルケニル、ヘテロシクロアルキル、ヘテロシクロアルケニル、アリール、又はヘテロアリールであり、ここで前記アルキル、シクロアルキル、シクロアルケニル、ヘテロシクロアルキル、ヘテロシクロアルケニル、アリール、ヘテロアリールは、場合により1つ以上のReで置換されており、
Reは、H、D、アルキル、アルケニル、アルキニル、ハロ、シアノ、アミン、ニトロ、ヒドロキシ、C(O)NHOH、アルコキシ、アルコキシアルキル、ハロアルキル、ヒドロキシアルキル、アミノアルキル、アルキルカルボニル、アルコキシカルボニル、アルキルカルボニルアミノ、アルキルアミノ、=O、ハロ-アルキルアミノ、シクロアルキル、シクロアルケニル、ヘテロシクロアルキル、ヘテロシクロアルケニル、アリール、又はヘテロアリールであり、
Z1は、結合、(CH2)p、N(H)、O、S、C(O)、S(O2)、OC(O)、C(O)O、OSO2、S(O2)O、C(O)S、SC(O)、C(O)C(O)、C(O)N(H)、N(H)C(O)、S(O2)N(H)、N(H)S(O2)、OC(O)O、OC(O)S、OC(O)N(H)、N(H)C(O)O、N(H)C(O)S、N(H)C(O)N(H)、(CH2)pN(H)(CH2)q、(CH2)pN(H)C(O)(CH2)q、(CH2)pC(O)N(H)(CH2)q、OC(O)N(H)(CH2)p+1N(H)(CH2)q、二価アルケニル基、又は二価アルキニル基であり、
Lは、結合、アルキレン、アルケニレン、アルキニレン、シクロアルキレン、シクロアルケニレン、ヘテロシクロアルキレン、ヘテロシクロアルケニレン、アリーレン、又はヘテロアリーレンであり、ここで前記アルキレン、シクロアルキレン、シクロアルケニレン、ヘテロシクロアルキレン、ヘテロシクロアルケニレン、アリーレン、又はヘテロアリーレンは、場合により1つ以上のRdで置換されており、
Y、W、W1、及びW2の各々は、独立に、CH又はNであり、
W3はO又はN(Ra)であり、
VはN、C、又はCHであり、
R9基の2つは、それらが結合している原子と共に、場合によりシクロアルキル又はヘテロシクロアルキルを形成してもよく、ここでR9の前記シクロアルキル又はヘテロシクロアルキルは、場合により1つ以上のRdで置換されており、
R2基の2つは、それらが結合している原子と共に、場合によりシクロアルキル又はヘテロシクロアルキルを形成してもよく、ここでR2の前記シクロアルキル又はヘテロシクロアルキルは、場合により1つ以上のRdで置換されており、
R10基の2つは、それらが結合している原子と共に、場合によりシクロアルキル又はヘテロシクロアルキルを形成してもよく、ここでR10の前記シクロアルキル又はヘテロシクロアルキルは、場合により1つ以上のRdで置換されており、
R11及びR12基は、それらが結合している原子と共に、場合によりシクロアルキル又はヘテロシクロアルキルを形成してもよく、ここでR11又はR12の前記シクロアルキル又はヘテロシクロアルキルは、場合により1つ以上のRdで置換されており、
R10及びR2基は、それらが結合している原子と共に、場合によりヘテロシクロアルキルを形成してもよく、ここでR10又はR2の前記ヘテロシクロアルキルは、場合により1つ以上のRdで置換されており、
R4及び-Z1-L-R6基は、それらが結合している原子と共に、場合によりシクロアルキル、シクロアルケニル、ヘテロシクロアルキル、ヘテロシクロアルケニル、アリール、又はヘテロアリールを形成してもよく、ここでR 4 、-Z 1 -L-R 6 基及びそれらが結合している原子から形成される前記シクロアルキル、シクロアルケニル、ヘテロシクロアルキル、ヘテロシクロアルケニル、アリール、又はヘテロアリールは、場合により1つ以上のRdで置換されており、
Rb及びRc基は、それらが結合している原子と共に、場合によりシクロアルキル、又はヘテロシクロアルキルを形成してもよく、ここでRb及びRcの前記シクロアルキル又はヘテロシクロアルキルは、場合により1つ以上のReで置換されており、
Rd基の2つは、それらが結合している原子と共に、場合によりシクロアルキル、又はヘテロシクロアルキルを形成してもよく、ここでRdの前記シクロアルキル又はヘテロシクロアルキルは、場合により1つ以上のReで置換されており、
Re基の2つは、それらが結合している原子と共に、場合によりシクロアルキル又はヘテロシクロアルキルを形成してもよく、ここでReの前記シクロアルキル又はヘテロシクロアルキルは、場合によりH、D、アルキル、アルケニル、アルキニル、ハロ、シアノ、アミン、ニトロ、ヒドロキシ、C(O)NHOH、アルコキシ、アルコキシアルキル、ハロアルキル、ヒドロキシアルキル、アミノアルキル、アルキルカルボニル、アルコキシカルボニル、アルキルカルボニルアミノ、アルキルアミノ、=O、ハロ-アルキルアミノ、シクロアルキル、シクロアルケニル、ヘテロシクロアルキル、ヘテロシクロアルケニル、アリール、又はヘテロアリールから選択される1つ以上の基で置換されており、
j及びkの各々は、独立に、0、1、2、3、4、5、6、7、又は8であり、
m、n、p、及びqの各々は、独立に、0、1、2、3、又は4である)
若しくはそのN-酸化物、又は前記式(A)の化合物若しくはそのN-酸化物の薬学的に許容可能な塩、溶媒和物、互変異性体、立体異性体、若しくは同位体形態。 Compound of formula (A)
Q1 is a 7-membered heterocycloalkyl, a 7-membered heterocycloalkenyl, or a 7-membered heteroaryl;
Q2 is aryl or heteroaryl;
Q3 is cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl;
Q4 is,
R1 , R2 , R3 , R4 , R5 , R6 , R7 , R8, R9 , R10 , R11 , and R12 are each independently selected from H, D, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, halo, nitro, =O , cyano, ORa , SRa , alkyl- Ra , NH( CH2 ) pRa , C(O) Ra , S(O) Ra , SO2Ra , C(O) ORa , OC(O) Ra , NRbRc , P(O) RbRc , alkyl-P(O) RbRc , C (O)N( Rb ) Rc, N( Rb )C( O ) Rc , S(O)(=N( Rb ) )) Rc , -N=S(O )RbRc, SO2N(Rb)Rc, or N(Rb)SO2Rc , wherein said cycloalkyl , cycloalkenyl , heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl are optionally substituted with one or more Rd ;
R a , R b , R c and R d are independently H, D, alkyl, alkenyl, alkynyl, halo, cyano, amine, nitro, hydroxy, C(O)NHOH, C(O)OH, C(O)NH 2 , alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, =O , halo-alkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl, wherein said alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl are optionally substituted with one or more Re ;
R e is H, D, alkyl, alkenyl, alkynyl, halo, cyano, amine, nitro, hydroxy, C(O)NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, =O , halo-alkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl;
Z1 is a bond, ( CH2 ) p , N(H), O, S, C(O), S( O2 ), OC(O), C(O)O, OSO2 , S( O2 )O, C(O)S, SC(O), C(O)C(O), C(O)N(H), N(H)C(O), S( O2 )N(H), N(H)S( O2 ), OC(O)O, OC(O)S, OC(O)N(H), N(H)C(O)O, N(H)C(O)S, N(H)C(O)N(H), ( CH2 ) pN (H)( CH2 ) q , ( CH2 ) pN (H)C(O)( CH2 ) q , ( CH2 ) pC (O)N(H)( CH2 ) q , OC(O)N(H)( CH2 ) p+1N (H)( CH2 ) q , a divalent alkenyl group, or a divalent alkynyl group;
L is a bond, alkylene , alkenylene, alkynylene , cycloalkylene , cycloalkenylene, heterocycloalkylene , heterocycloalkenylene , arylene , or heteroarylene , wherein said alkylene , cycloalkylene , cycloalkenylene , heterocycloalkylene , heterocycloalkenylene , arylene , or heteroarylene is optionally substituted with one or more Rd ;
Each of Y, W, W1 , and W2 is independently CH or N;
W3 is O or N(R a );
V is N, C, or CH;
Two of the R 9 groups together with the atom to which they are attached may optionally form a cycloalkyl or heterocycloalkyl, where the cycloalkyl or heterocycloalkyl of R 9 is optionally substituted with one or more R d ;
Two of the R2 groups together with the atom to which they are attached may optionally form a cycloalkyl or heterocycloalkyl, where said cycloalkyl or heterocycloalkyl of R2 is optionally substituted with one or more Rd ;
Two of the R 10 groups together with the atom to which they are attached may optionally form a cycloalkyl or heterocycloalkyl, where the cycloalkyl or heterocycloalkyl of R 10 is optionally substituted with one or more R d ;
The R 11 and R 12 groups together with the atom to which they are attached may optionally form a cycloalkyl or heterocycloalkyl, wherein said cycloalkyl or heterocycloalkyl of R 11 or R 12 is optionally substituted with one or more R d ;
The R 10 and R 2 groups together with the atom to which they are attached may optionally form a heterocycloalkyl, where said heterocycloalkyl of R 10 or R 2 is optionally substituted with one or more R d ;
R 4 and -Z 1 -LR 6 groups together with the atom to which they are attached may optionally form a cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl, wherein the cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl formed by R 4 , -Z 1 -LR 6 groups and the atom to which they are attached is optionally substituted with one or more R d ;
The R b and R c groups together with the atom to which they are attached may optionally form a cycloalkyl, or heterocycloalkyl, where the cycloalkyl or heterocycloalkyl of R b and R c is optionally substituted with one or more Re ;
Two of the R d groups together with the atom to which they are attached may optionally form a cycloalkyl, or heterocycloalkyl, where the cycloalkyl or heterocycloalkyl of R d is optionally substituted with one or more Re ;
Two of the R e groups together with the atom to which they are attached may optionally form a cycloalkyl or heterocycloalkyl, where said cycloalkyl or heterocycloalkyl of R e is optionally substituted with one or more groups selected from H, D, alkyl, alkenyl, alkynyl, halo, cyano, amine, nitro, hydroxy, C(O)NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, =O , halo-alkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl;
Each of j and k is independently 0, 1, 2, 3, 4, 5, 6, 7, or 8;
Each of m, n, p, and q is independently 0, 1, 2, 3, or 4.
or an N-oxide thereof, or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopic form of said compound of formula (A) or an N-oxide thereof.
Z2は、-O-、-CH2-、-C(O)-、-N(Ra)-、-S-、-S(O)-、-S(O2)-、-S(O)(=N(Ra))-、-P(O)(Ra)-であり、Z2のRaは、独立に、H、D、C1~C6アルキル、C2~C6アルケニル、C1~C6アルキルカルボニル、C1~C6アルコキシカルボニル、C3~C6シクロアルキル、5~8員単環式ヘテロシクロアルキル、C6~C14アリール、又は5~8員単環式ヘテロアリールであり、ここで前記C1~C6アルキル、C3~C6シクロアルキル、5~8員単環式ヘテロシクロアルキル、C6~C14アリール、5~8員単環式ヘテロアリールは、場合により1つ以上のReで置換されており、
Aは、-(CR2R2)r-又は-O-であり、rは、0、1、2、又は3であり、
各R2は、独立に、H、-(C1~C4)アルコキシ、場合により-(C1~C4)アルコキシで置換されている-(C1~C4)アルキルであるか、又は
R2基の2つは、それらが結合している同じ炭素原子と共に、-(C3~C6)シクロアルキル若しくは4~6員ヘテロシクロアルキルを形成し、ここで前記-(C3~C6)シクロアルキル又は4~6員ヘテロシクロアルキルは、場合により-(C1~C4)アルキル、-(C1~C4)ハロアルキル又はオキセタニルから選択される1つ以上の基で置換されている、
請求項1に記載の化合物若しくはそのN-酸化物、又はその薬学的に許容可能な塩、溶媒和物、互変異性体、立体異性体、若しくは同位体形態。 Represented by formula (B):
Z2 is -O-, -CH2- , -C(O)-, -N(R a )-, -S-, -S(O)-, -S( O2 )-, -S(O)(=N(R a ))-, -P(O)(R a )-, R a of Z2 is independently H, D, C1 - C6 alkyl, C2- C6 alkenyl, C1 - C6 alkylcarbonyl, C1 - C6 alkoxycarbonyl, C3 - C6 cycloalkyl, 5-8 membered monocyclic heterocycloalkyl, C6 - C14 aryl, or 5-8 membered monocyclic heteroaryl, wherein said C1 - C6 alkyl, C3 - C6 cycloalkyl, 5-8 membered monocyclic heterocycloalkyl, C6 - C14 aryl, 5-8 membered monocyclic heteroaryl are optionally substituted with one or more Re ;
A is -( CR2R2 ) r- or -O-, where r is 0, 1, 2 , or 3;
each R2 is independently H, -( C1 - C4 )alkoxy, -( C1 - C4 )alkyl optionally substituted with -( C1 - C4 )alkoxy;
two of the R2 groups together with the same carbon atom to which they are attached form a -( C3 - C6 )cycloalkyl or a 4- to 6-membered heterocycloalkyl , wherein said -( C3 - C6 )cycloalkyl or a 4- to 6-membered heterocycloalkyl is optionally substituted with one or more groups selected from -( C1 - C4 )alkyl, -( C1 - C4 )haloalkyl or oxetanyl;
10. The compound of claim 1 or an N-oxide thereof, or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopic form thereof.
請求項2に記載の化合物若しくはそのN-酸化物、又はその薬学的に許容可能な塩、溶媒和物、互変異性体、立体異性体、若しくは同位体形態。 Represented by formula (C):
3. The compound of claim 2, or an N-oxide thereof, or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopic form thereof.
R5は、独立に、ニトロ、ハロ、又は-SO2Raであり、R5のRaは、-(C1~C4)アルキル又は-(C1~C4)ハロアルキルであり、
Z1は、結合、NH、N(H)(CH2)q、O、S、又は-(C1~C4)アルキレンであり、qは、1、2、又は3であり、
Lは、結合、又は場合により-(C3~C6)シクロアルキルで置換されている-(C1~C4)アルキレンであり、
R6は、H、D、-P(O)(N(CH3)2)(OEt)、-(C3~C6)シクロアルキル、フェニル、5~7員ヘテロシクロアルキル、8~10員二環式環であり、ここで前記-(C3~C6)シクロアルキル、フェニル、5~7員ヘテロシクロアルキル、又は8~10員二環式環は、場合によりハロ、-OH、=O、-CN、-COOH、-NH2、-N(CH3)2 、-(C1~C4)アルキル、-(C1~C4)アルコキシ、-(C1~C4)ハロアルコキシ、シクロプロピル、4~6員ヘテロシクロアルキル、-CH2P(O)(OH)2、-CH2P(O)((C1~C4)アルコキシ)2、-P(O)((C1~C4)アルキル)2、又は-N=S(O)((C1~C4)アルキル)2から選択される1つ以上の基で置換されている、
請求項3に記載の化合物若しくはそのN-酸化物、又はその薬学的に許容可能な塩、溶媒和物、互変異性体、立体異性体、若しくは同位体形態。 Represented by formula (D):
R5 is independently nitro, halo, or -SO2R a , where R a of R5 is -( C1 - C4 )alkyl or -( C1 - C4 )haloalkyl;
Z 1 is a bond, NH, N(H)(CH 2 ) q , O, S, or -(C 1 -C 4 )alkylene, where q is 1, 2, or 3;
L is a bond or -(C 1 -C 4 )alkylene optionally substituted with -(C 3 -C 6 )cycloalkyl;
R 6 is H, D, -P(O)(N(CH 3 ) 2 )(OEt), -(C 3 -C 6 )cycloalkyl, phenyl, 5- to 7-membered heterocycloalkyl , 8- to 10-membered bicyclic ring, wherein said -(C 3 -C 6 )cycloalkyl, phenyl, 5- to 7-membered heterocycloalkyl , or 8- to 10-membered bicyclic ring is optionally selected from halo, -OH, ═O, -CN, -COOH, -NH 2 , -N(CH 3 ) 2 , -( C 1 -C 4 )alkyl, -(C 1 -C 4 )alkoxy, -(C 1 -C 4 )haloalkoxy, cyclopropyl, 4- to 6-membered heterocycloalkyl , -CH 2 P(O)(OH) 2 , -CH 2 P(O)((C 1 -C 4 )alkoxy) 2 , -P(O)((C 1 -C 4 )alkyl) 2 , or -N=S(O)((C 1 -C 4 )alkyl) 2 ;
4. The compound of claim 3, or an N-oxide thereof, or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopic form thereof.
(R)-N-((4-(((1,4-ジオキサン-2-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
(S)-N-((4-(((1,4-ジオキサン-2-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
(S)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(4-メチル-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
N-((4-((((S)-1,4-ジオキサン-2-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-((S)-4-メチル-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
N-((4-((((R)-1,4-ジオキサン-2-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-((S)-4-メチル-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
(R)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(4-メチル-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
N-((4-((((S)-1,4-ジオキサン-2-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-((R)-4-メチル-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
N-((4-((((R)-1,4-ジオキサン-2-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-((R)-4-メチル-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(4,4-ジフルオロ-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((3-ニトロ-4-(((テトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)フェニル)スルホニル)ベンズアミド、
(R)-N-((4-(((1,4-ジオキサン-2-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(4,4-ジフルオロ-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
(S)-N-((4-(((1,4-ジオキサン-2-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(4,4-ジフルオロ-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-(((4-フルオロテトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミド、
(S)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-(((2-フルオロ-1,4-ジオキサン-2-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミド、
(R)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-(((2-フルオロ-1,4-ジオキサン-2-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミド、
(S)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-N-((4-(((4-フルオロテトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-2-(4-メチル-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-N-((4-((((R)-2-フルオロ-1,4-ジオキサン-2-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-2-((S)-4-メチル-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-N-((4-((((S)-2-フルオロ-1,4-ジオキサン-2-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-2-((S)-4-メチル-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
(R)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-N-((4-(((4-フルオロテトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-2-(4-メチル-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-N-((4-((((R)-2-フルオロ-1,4-ジオキサン-2-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-2-((R)-4-メチル-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-N-((4-((((S)-2-フルオロ-1,4-ジオキサン-2-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)-2-((R)-4-メチル-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)ベンズアミド、
4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(4,4-ジフルオロ-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-(((4-フルオロテトラヒドロ-2H-ピラン-4-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミド、
(S)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(4,4-ジフルオロ-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-(((2-フルオロ-1,4-ジオキサン-2-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミド、又は
(R)-4-(4-((4'-クロロ-5,5-ジメチル-3,4,5,6-テトラヒドロ-[1,1'-ビフェニル]-2-イル)メチル)ピペラジン-1-イル)-2-(4,4-ジフルオロ-3,4-ジヒドロ-2H-ピロロ[3',2':5,6]ピリド[2,3-b][1,4]オキサゼピン-1(7H)-イル)-N-((4-(((2-フルオロ-1,4-ジオキサン-2-イル)メチル)アミノ)-3-ニトロフェニル)スルホニル)ベンズアミド
である、請求項1に記載の化合物若しくはそのN-酸化物、又はその薬学的に許容可能な塩、溶媒和物、互変異性体、立体異性体、若しくは同位体形態。 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
(R)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
(S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
(S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
N-((4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-((S)-4-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
N-((4-((((R)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-((S)-4-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
(R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
N-((4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-((R)-4-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
N-((4-((((R)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-((R)-4-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4,4-difluoro-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
(R)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4,4-difluoro-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
(S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4,4-difluoro-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,
(S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((2-fluoro-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,
(R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((2-fluoro-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,
(S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(4-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((R)-2-fluoro-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((S)-4-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((S)-2-fluoro-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((S)-4-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
(R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(4-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((R)-2-fluoro-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((R)-4-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((S)-2-fluoro-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((R)-4-methyl-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,
4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4,4-difluoro-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,
(S)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4,4-difluoro-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((2-fluoro-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide, or
2. The compound of claim 1, which is (R)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4,4-difluoro-3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((2-fluoro-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide, or an N-oxide thereof, or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopic form thereof.
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